Benzopiperidine derivatives

ABSTRACT

Benzopiperidine derivatives represented by formula (I), salts thereof or hydrates thereof, processes for producing the same and drugs comprising the same: 
     
       
         
         
             
             
         
       
     
     wherein the variables are as described in the specification. These compounds are useful as drugs efficacious in the prevention and treatment of these various inflammatory diseases and immunologic diseases, such as rheumatoid arthritis, atopic dermatitis, psoriasis, asthma, and rejection reaction accompanying organ transplantation.

This application is the national phase under 35 U.S.C. §371 of prior PCTInternational Application No. PCT/JP97/02787 which has an Internationalfiling date of Aug. 8, 1997 which designated the United States ofAmerica.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to benzopiperidine derivatives, salts thereof orhydrates thereof, which are useful in the prevention and treatment ofimmunologic diseases, etc., drugs containing the same, processes forproducing the same and intermediates thereof.

2. Prior Art

In recent years, the participation adhesion molecules such as ICAM-1,VCAM-1 and E-selectin participate in the processes of extravascularinfiltration of leukocytes into inflammatory tissues, metastasis ofcancer cells, recognition of antigens by immunocytes and proliferationof immunocytes has come to be regarded as highly important. For example,rheumatoid arthritis is actually associated with the promoted expressionof adhesion molecules in joints, the infiltration of lymphocytes intojoint synovial membranes and neutrophil infiltration into the synovialfluid. It has been also reported that adhesion molecules participate inasthma, nephritis, ischemic reflow disorders, psoriasis, atopicdermatitis, the rejection reaction accompanying organ transplantation,and cancer metastasis. Therefore, it is expected that the inflammatoryimmunologic diseases such as asthma, nephritis, psoriasis, atopicdermatitis, inflammation, ischemic reflow disorders and the rejectionreaction accompanying organ transplantation, autoimmune diseases such asrheumatism and collagen disease, and cancer metastasis can be inhibitedby regulating the adhesion of leukocytes, neutrophilis, cancer cells,etc. to intravascular endothelial cells and controlling the antigenrecognition process.

When treating various inflammatory diseases and immune diseases such asrheumatoid arthritis, it has been a common practice to suppress theinflammation by the use of nonsteroidal antiinflammatory drugs (NSAID)such as indomethacin and ibuprofen, and steroids, i.e., “symptomatictreatments”.

Recently, attempts have been also made to use immunomodulators such asD-penicillamine which is a remedy for rheumatism and Wilson's disease,and levamisole which is an immunopotentiator activating T cells, inorder to ameliorate immunopathy at the early stage, i.e., “causaltreatments”.

However, NSAIDs such as indomethacin have serious side effects such asgastric ulceration. Moreover, it is considered that these drugs are notefficacious against tissue disorders or the pathological progressionassociated with chronic inflammation. With respect to steroids too, theproblem of serious side effects frequently arises.

On the other hand, hitherto no immunomodulator has been knownsatisfactory both in its therapeutic effects and side effects.Accordingly, the development of excellent drugs suitable for bothsymptomatic and causal treatments has been urgently required.

As compounds having similar structures to those of the compounds of thepresent invention, it was disclosed in JP-A-60-115524 that1,4-diazaphenothiazine derivatives have 5-lipoxygenase inhibitoryeffects. However, this patent provides few examples, despite its broadclaims. That is to say, the claims thereof are not clearly supported bythe description in the specification.

Furthermore, the above-mentioned patent neither states nor suggests thatthese compounds are efficacious in the prevention and treatment ofvarious diseases owing to the cell adhesion inhibitory effects thereof,as clarified in the present invention.

On the other hand, compounds analogous to the compounds of the presentinvention are reported as nerve relaxants in J. Med. Chem., 16 (4), 564(1983) and as antibacterial agents, insecticides and herbicides in U.S.Pat. Nos. 3,663,543, 3,746,707, 3,808,208, 3,821,213 and 3,845,044.

SUMMARY OF THE INVENTION

The present inventors have conducted extensive studies in order toprovide drugs efficacious in the prevention and treatment of thesevarious inflammatory diseases and immunologic diseases such asrheumatoid arthritis, atopic dermatitis, psoriasis, asthma and therejection reaction accompanying organ transplantation. As a result, theyhave succeeding in discovering that benzopiperidine derivatives withnovel structures have excellent antiinflammatory and anti-immunologicdisease effects, thus completing the present invention.

Accordingly, the present invention relates to benzopiperidinederivatives represented by the following formula (I), salts thereof orhydrates thereof, processes for producing the same and drugs comprisingthe same:

wherein R¹ to R³ may be the same or different and each represents:

1) hydrogen,

2) optionally substituted lower alkyl;

3) optionally substituted lower alkenyl;

4) optionally substituted lower alkynyl;

5) optionally substituted lower cycloalkyl;

6) optionally substituted lower cycloalkenyl;

7) optionally substituted C₂₋₆ alkoxy;

8) a group represented by the following formula:

 wherein X and Y represent each optionally substituted lower alkyleneoptionally having a heteroatom, optionally substituted lower alkenyleneoptionally having a heteroatom or optionally substituted loweralkynylene optionally having a heteroatom; l and m may be the same ordifferent and each represents 0 or 1; the ring A represents anoptionally substituted cycloalkyl ring optionally having one or moreheteroatoms; the ring B represents a ring optionally having one or moredouble bonds in the ring which is selected from owing following:

a) an optionally substituted cycloalkyl ring optionally having aheteroatom;

b) an optionally substituted bicycloalkyl ring optionally having aheteroatom, wherein the different atoms (bridgehead atoms) in the ring Bare bonded to each other via an optionally substituted C₁ or higheralkylene group optionally having a heteroatom; or

c) an optionally substituted spiro-hydrocarbon ring optionally having aheteroatom, wherein the both ends of an optionally substituted C₁ orhigher alkylene group optionally having a heteroatom are bonded to acarbon atom (bridgehead carbon atom) in the ring B;

9) a group represented by the following formula:

 wherein

X¹ represents an optionally substituted lower alkylene optionally havinga heteroatom, optionally substituted lower alkenylene optionally havinga heteroatom or optionally substituted lower alkynylene optionallyhaving a heteroatom;

l¹ is 0 or 1;

the ring A¹ represents:

a) an optionally substituted cycloalkyl ring optionally having one ormore heteroatoms;

b) an optionally substituted cycloalkenyl ring optionally having one ormore heteroatoms; or

c) an optionally substituted spiro-hydrocarbon ring optionally having aheteroatom, wherein the both ends of an optionally substituted C₁ orhigher alkylene group optionally having a heteroatom are bonded to acarbon atom (bridgehead carbon atom) in the ring A¹; or

10) a group represented by the following formula:

 wherein

X² represents an optionally substituted lower alkylene optionally havinga heteroatom, optionally substituted lower alkenylene optionally havinga heteroatom or optionally substituted lower alkynylene optionallyhaving a heteroatom;

l² is 0 or 1;

Q represents:

a) heteroaryl consisting of one or more optionally substituted rings oraryl consisting of one or more optionally substituted rings;

b) optionally substituted quaternary ammonio;

c) a group represented by the following formula:

 wherein R⁵ and R⁶ may be the same or different and each representshydrogen or lower alkyl;

d) lower acyl;

e) lower acyloxy;

f) carbamoyl;

g) a group represented by the following formula:

 wherein R⁷ and R⁸ may be the same or different and each representshydrogen, lower alkyl, a group represented by the formula:

 wherein R⁷¹ represents lower alkyl, trifluoromethyl, aryl or a grouprepresented by the formula:

 wherein R⁷² and R⁷³ may be the same or different and each representshydrogen, lower alkyl, lower cycloalkyl or aryl;

a group represented by the following formula:

 wherein R⁸¹ represents hydrogen, lower alkyl or aryl;

a group represented by the following formula:

 wherein R⁷⁴ and R⁷⁵ may be the same or different and each representshydrogen or lower alkyl;

a group represented by the following formula:

 wherein R⁷⁶ represents hydrogen, lower alkyl, cyano, pyridyl or loweralkylsulfonyl; R⁷⁷ represents hydrogen or lower alkyl, or an aminoprotecting group;

h) protected hydroxy;

i) a group represented by the following formula:

—S—R⁸²

 wherein R⁸² represents hydrogen, lower alkyl or a mercapto protectinggroup;

j) carboxy;

k) protected carboxy;

l) a group represented by the following formula:

 wherein W represents oxygen or sulfur; R⁸³ and R⁸⁴ may be the same ordifferent and each represents hydrogen, lower alkyl, lower cycloalkyl,cyano, aryl or a group represented by the following formula:

—SO₂R⁸⁵

 wherein R⁸⁵ represents hydrogen, hydroxy, lower alkyl or aryl; or R⁸³and R⁸⁴ may together form an optionally substituted lower cycloalkyloptionally having one or more heteroatoms;

m) sulfonyl;

n) sulfonylamido;

o) azido;

p) formyl;

q) a group represented by the following formula:

 wherein R⁸⁶, R⁸⁷ and R⁸⁸ may be the same or different and eachrepresents hydrogen, aryl, heteroaryl, optionally substituted loweralkyl, hydroxy(lower alkyl), cyano, amino, nitro, acetyl or a grouprepresented by the following formula:

—SO₂R⁸⁹

 wherein R⁸⁹ represents aryl, hydroxy, optionally substituted loweralkyl, trifluoromethyl or amino; or R⁸⁶ and R⁸⁷ may together form anoptionally substituted lower cycloalkyl optionally having one or moreheteroatoms;

r) guanidino;

s) hydrazino;

t) isocyano;

u) cyanate;

v) isocyanate;

w) thiocyanate;

x) isothiocyanate;

y) nitroso; or

z) a group represented by the following formula:

wherein R⁹⁰ and R⁹¹ each represents hydrogen or lower alkyl, providedthat the case where R¹ to R³ each represents methyl in the case 2) ofthe above definition thereof is excluded;

R represents:

1) hydrogen;

2) lower alkyl;

3) optionally substituted arylalkyl;

4) optionally substituted heteroarylalkyl;

5) an amino protecting group;

6) a group represented by the following formula:

 wherein X³ represents an optionally substituted lower alkyleneoptionally having a heteroatom, optionally substituted lower alkenyleneoptionally having a heteroatom or optionally substituted loweralkynylene optionally having a heteroatom; R⁹ and R¹⁰ may be the same ordifferent and each represents hydrogen, lower alkyl or an aminoprotecting group; or

7) a group represented by the following formula:

—X⁴—CO₂R¹¹

 wherein X⁴ represents optionally substituted lower alkylene optionallyhaving a heteroatom, optionally substituted lower alkenylene optionallyhaving a heteroatom or optionally substituted lower alkynyleneoptionally having a heteroatom; R¹¹ represents hydrogen, lower alkyl ora carboxyl protecting group;

E represents N or a group represented by the following formula:

C—R⁴

 wherein R⁴ has the same meaning as 1 to 11) as defined above withrespect to R¹ to R³;

Z represents O, S, SO, SO₂ or a group represented by the followingformula:

N—R¹²

 wherein R¹² represents hydrogen, lower alkyl or an amino protectinggroup;

the ring G represents an optionally substituted heteroaryl ring havingone or more nitrogen atoms;

provided that the following cases are excluded:

a) that in which R¹ to R³ are each hydrogen, E is CH, Z is O, S, or SO₂and the ring G is an unsubstituted (i.e., all of the substituents beinghydrogen atoms) heteroaryl ring having one or more nitrogen atoms;

b) that in which R¹ to R³ are each hydrogen, E is CH, Z is O, S, SO₂ orNH and the substituent(s) of the ring G is optionally substitutedphenyl, pyridinyl, thienyl, nitro, cyano, halogeno, acetyl, methyl,ethyl, t-butyl, ethoxy, N-methylpiperazyl, naphthyl, optionallyprotected carboxyalkyl or amino;

c) that in which R¹ to R³ are each hydrogen, E is CH, Z is NH and thering G is unsubstituted (i.e., all of the substituents are hydrogenatoms) pyridazine; and

d) that in which R¹ to R³ are each hydrogen, E is CH, R is a group otherthan hydrogen, Z is NR^(12′) (R^(12′) being lower alkyl or an aminoprotecting group) and the ring G is an optionally substituted heteroarylring optionally having one or more nitrogen atoms.

Now, the contents of the present invention will be described in detail.

Although the contents of the present invention are as has been describedabove, the invention preferably relates to benzopiperidine derivativesof the above formula (I), wherein Z is S, salts thereof or hydratesthereof, processes for producing the same and drugs comprising the same,and benzopiperidine derivatives of the above formula (I), wherein thering G is an optionally substituted pyrazine ring, salts thereof orhydrates thereof, processes for producing the same and drugs comprisingthe same. Still more preferably, the invention relates tobenzopiperidine derivatives represented by the following formula (II),salts thereof or hydrates thereof, processes for producing the same anddrugs comprising the same:

wherein

R, E, Z and the ring G are each as defined above;

U represents:

1) a group represented by the following formula:

 wherein X, Y, l, m and the rings A and B are each as defined above; or

2) a group represented by the following formula:

 wherein X¹, l¹ and the ring A¹ are each as defined above.

Still more preferably, the invention relates to benzopiperidinederivatives represented by the above formula (II), salts thereof orhydrates thereof, processes for producing the same and drugs comprisingthe same, wherein U in the formula (II) represents:

1) a group represented by the following formula:

 wherein

X, Y, l, m and the ring B are each as defined above; and

the ring A² represents an optionally substituted cycloalkyl ring havingone or more heteroatoms; or

2) a group represented by the following formula:

 wherein

X¹ and l¹ are each as defined above; and

the ring A³ represents:

a) an optionally substituted cycloalkyl ring having one or moreheteroatoms;

b) an optionally substituted cycloalkenyl ring having one or moreheteroatoms; or

c) an optionally substituted spiro-hydrocarbon ring having one or moreheteroatoms, wherein both ends of an optionally substituted C. or higheralkylene group optionally having a heteroatom are bonded to a carbonatom (bridgehead carbon atom) in the ring A³. Particularly preferably,it relates to benzopiperidine derivatives represented by the followingformula (III), salts thereof or hydrates thereof, processes forproducing the same and drugs comprising the same:

 wherein

R, E, Z and the ring G are each as defined above;

U¹ represents:

1) a group represented by the following formula:

 wherein Y, m and the rings A² and B are each as defined above; or

2) a group represented by the following formula:

wherein the ring A³ is as defined above. Still preferably, the inventionrelates to benzopiperidine derivatives represented by the followingformula (II) or (III), wherein the ring G is an optionally substitutedpyrazine ring, salts thereof or hydrates thereof, processes forproducing the same and drugs comprising the same. In the most desirablecase, the present invention relates to a benzopiperidine derivativeselected from among those represented by the following formulae 1) to3), its salt or hydrates thereof, a process for producing the same anddrugs comprising the same:

Although compounds are sometimes given as particular isomers instructural formulae herein for the sake of convenience, the compounds ofthe present invention are not restricted to the structural formulaegiven for the sake of convenience but involve all of the isomers andisomeric mixtures such as geometrical isomers occurring structurally,optical isomers depending on asymmetric carbon, stereoisomers andtautomers.

Next, the terms employed herein will be described in detail.

First, the definition of the formula (I) will be illustrated. R¹ to R⁴are each as defined above. (R⁴, which is a group defined in E and havingthe same meaning as those of R¹ to R³, is illustrated together with R¹to R³ herein).

The expression “optionally substituted” as used herein particularlymeans that the corresponding group may be substituted by substituent(s),for example, hydroxy; thiol; nitro; nitroso; morpholino; thiomorpholino;halogeno such as fluoro, bromo and iodo; nitrile; isocyano; cyanate;isocyanate; thiocyanate; isothiocyanate; azido; formyl; thioformyl;alkyl such as methyl, ethyl, propyl, isopropyl and butyl; alkenyl suchas vinyl, allyl and propenyl; alkynyl such as ethynyl, butynyl andpropargyl; alkoxy corresponding to lower alkyl such as methoxy, ethoxy,propoxy and butoxy; halogenoalkyl such as fluoromethyl, difluoromethyl,trifluoromethyl and fluoroethyl; hydroxyalkyl such as hydroxymethyl,hydroxyethyl and hydroxypropyl; guanidino; hydrazino; hydraozono;ureido; ureylene; amidino; formimidoyl; acetimidoyl; carbamoyl;thiocarbamoyl; carbamoylalkyl such as carbamoylmethyl andcarbamoylethyl; alkylcarbamoyl such as methylcarbamoyl anddimethylcarbamoyl; carbamido; sulfoamino; sulfamoyl; sulfamoylalkyl suchas sulfamoylmethyl and sulfamoylethyl; alkylsulfamoyl such asmethylsulfamoyl and dimethylsulfamoyl; sulfamido; N-alkylsulfamido suchas N-methylsulfamido and N-ethylsulfamido; arylsulfamido such asN-phenylsulfamido; alkanoyl such as acetyl, propionyl and butyryl;thioacetyl; amino; hydroxyamino; alkylamino such as methylamino,ethylamino and isopropylamino; dialkylamino such as dimethylamino,methylethylamino and diethylamino; acylamino such as acetylamino andbenzoylamino; aminoalkyl such as aminomethyl, aminoethyl andaminopropyl; carboxy; alkoxycarbonyl such as methoxycarbonyl,ethoxycarbonyl and propoxycarbonyl; alkoxycarbonylalkyl such asmethoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylmethyl,methoxycarbonylethyl, ethoxycarbonylethyl and propoxycarbonylethyl;alkyloxyalkyl such as methyloxymethyl, methyloxyethyl, ethyloxymethyland ethyloxyethyl; alkylthioalkyl such as methylthiomethyl,methylthioethyl, ethylthiomethyl and ethylthioethyl;aminoalkylaminoalkyl such as aminomethylaminomethyl andaminoethylaminomethyl; alkylcarbonyloxy such as methylcarbonyloxy,ethylcarbonyloxy and isopropylcarbonyloxy; arylalkoxyalkoxyalkyl such asoxymethyl and benzyloxyethyloxyethyl; hydroxyalkoxyalkyl such ashydroxyethyloxymethyl and hydroxyethyloxyethyl; arylalkoxyalkyl such asbenzyloxymethyl, benzyloxyethyl and benzyloxypropyl; quaternary ammoniosuch as trimethylammonio, methylethylmethylammonio and triethylammonio;cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;cycloalkenyl such as cyclopropenyl, cyclobutenyl, cyclopentenyl andcyclohexenyl; aryl such as phenyl, pyridinyl, thienyl, furyl andpyrrolyl; alkylthio such as methylthio, ethylthio, propylthio andbutylthio; arylthio such as phenylthio, pyridinylthio, thienylthio,furylthio and pyrrolylthio; aryl(lower alkyl) such as benzyl, trityl anddimethoxytrityl; sulfonyl and substituted sulfonyl such as mesyl andp-toluenesulfonyl; sulfinyl and substituted sulfinyl such asmethylsulfinyl, ethylsulfinyl and phenylsulfinyl; sulfenyl andsubstituted sulfenyl such as methylsulfenyl, ethylsulfenyl andphenylsulfenyl; aryloyl such as benzoyl, toluoyl and cinnamoyl;halogenoaryl such as fluorophenyl and bromophenyl; and oxyalkoxy such asmethylenedioxy.

The expression “having one or more substituents” means that thecorresponding group may have an arbitrary combination of thesesubstituents. For example, the present invention involves alkyl,alkenyl, alkynyl, alkoxy, etc. substituted by hydroxy, thiol, nitro,morpholino, thiomorpholino, halogeno, nitrile, azido, formyl, ammonio,alkylamino, dialkylamino, carbamoyl, sulfonyl, etc.

The expression “optionally substituted” as used herein below has themeaning as defined above.

The term “lower alkyl group” means a linear or branched C₁₋₆ alkylgroup. Particular examples thereof include methyl [methyl being excludedfrom the definition 2) of R¹ to R⁴], ethyl, n-propyl, i-propyl, n-butyl,i-butyl, sec-butyl, t-butyl, n-pentyl, i-pentyl, sec-pentyl, t-pentyl,neopentyl, 1-methylbutyl, 2-methylbutyl, 1,1-dimethylpropyl,1,2-dimethylpropyl, n-hexyl, i-hexyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,2,2,-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl,3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl,1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropylgroups. Preferable examples thereof include methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, i-pentyl,sec-pentyl, t-pentyl, neopentyl, 1-methylbutyl, 2-methylbutyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, n-hexyl and i-hexyl groups.Still more preferable ones are methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, sec-butyl and t-butyl groups and the most desirableones are methyl, ethyl, n-propyl and i-propyl groups.

The term “lower alkenyl group” means a linear or branched C₁₋₆ alkenylgroup which is the residue of a compound having a double bond in theabove-mentioned alkyl group. Particular examples thereof includeethenyl, 1-propen-1-yl, 2-propen-1-yl, 3-propen-1-yl, 1-buten-1-yl,1-buten-2-yl, 1-buten-3-yl, 1-buten-4-yl, 2-buten-1-yl, 2-buten-2-yl,1-methyl-1-propen-1-yl, 2-methyl-1-propen-1-yl, 1-methyl-2-propen-1-yl,2-methyl-2-propen-1-yl, 1-methyl-1-buten-1-yl, 2-methyl-1-buten-1-yl,3-methyl-1-buten-1-yl, 1-methyl-2-buten-1-yl, 2-methyl-2-buten-1-yl,3-methyl-2-buten-1-yl, 1-methyl-3-buten-1-yl, 2-methyl-3-buten-1-yl,3-methyl-3-buten-1-yl, 1-ethyl-1-buten-1-yl, 2-ethyl-1-buten-1-yl,3-ethyl-1-buten-1-yl, 1-ethyl-2-buten-1-yl, 2-ethyl-2-buten-1-yl,3-ethyl-2-buten-1-yl, 1-ethyl-3-buten-1-yl, 2-ethyl-3-buten-1-yl,3-ethyl-3-buten-1-yl, 1,1-dimethyl-1-buten-1-yl,1,2-dimethyl-1-buten-1-yl, 1,3-dimethyl-1-buten-1-yl,2,2-dimethyl-1-buten-1-yl, 3,3-dimethyl-1-buten-1-yl,1,1-dimethyl-2-buten-1-yl, 1,2-dimethyl-2-buten-1-yl,1,3-dimethyl-2-buten-1-yl, 2,2-dimethyl-2-buten-1-yl,3,3-dimethyl-2-buten-1-yl, 1,1-dimethyl-3-buten-1-yl,1,2-dimethyl-3-buten-1-yl, 1,3-dimethyl-3-buten-1-yl,2,2-dimethyl-3-buten-1-yl, 3,3-dimethyl-3-buten-1-yl, 1-penten-1-yl,2-penten-1-yl, 3-penten-1-yl, 4-penten-1-yl, 1-penten-2-yl,2-penten-2-yl, 3-penten-2-yl, 4-penten-2-yl, 1-penten-3-yl,2-penten-3-yl, 1-penten-1-yl, 2-penten-1-yl, 3-penten-1-yl,4-penten-1-yl, 1-penten-2-yl, 2-penten-2-yl, 3-penten-2-yl,4-penten-2-yl, 1-penten-3-yl, 2-penten-3-yl, 1-methyl-1-penten-1-yl,2-methyl-1-penten-1-yl, 3-methyl-1-penten-1-yl, 4-methyl-1-penten-1-yl,1-methyl-2-penten-1-yl, 2-methyl-2-penten-1-yl, 3-methyl-2-penten-1-yl,4-methyl-2-penten-1-yl, 1-methyl-3-penten-1-yl, 2-methyl-3-penten-1-yl,3-methyl-3-penten-1-yl, 4-methyl-3-penten-1-yl, 1-methyl-4-penten-1-yl,2-methyl-4-penten-1-yl, 3-methyl-4-penten-1-yl, 4-methyl-4-penten-1-yl,1-methyl-1-penten-2-yl, 2-methyl-1-penten-2-yl, 3-methyl-1-penten-2-yl,4-methyl-1-penten-2-yl, 1-methyl-2-penten-2-yl, 2-methyl-2-penten-2-yl,3-methyl-2-penten-2-yl, 4-methyl-2-penten-2-yl, 1-methyl-3-penten-2-yl,2-methyl-3-penten-2-yl, 3-methyl-3-penten-2-yl, 4-methyl-3-penten-2-yl,1-methyl-4-penten-2-yl, 2-methyl-4-penten-2-yl, 3-methyl-4-penten-2-yl,4-methyl-4-penten-2-yl, 1-methyl-1-penten-3-yl, 2-methyl-1-penten-3-yl,3-methyl-1-penten-3-yl, 4-methyl-1-penten-3-yl, 1-methyl-2-penten-3-yl,2-methyl-2-penten-3-yl, 3-methyl-2-penten-3-yl, 4-methyl-2-penten-3-yl,1-hexen-1-yl, 1-hexen-2-yl, 1-hexen-3-yl, 1-hexen-4-yl, 1-hexen-5-yl,1-hexen-6-yl, 2-hexen-1-yl, 2-hexen-2-yl, 2-hexen-3-yl, 2-hexen-4-yl,2-hexen-5-yl, 2-hexen-6-yl, 3-hexen-1-yl, 3-hexen-2-yl and 3-hexen-3-ylgroups. Preferable examples thereof include ethenyl, 1-propen-1-yl,2-propen-1-yl, 3-propen-1-yl, 1-buten-1-yl, 1-buten-2-yl, 1-buten-3-yl,1-buten-4-yl, 2-buten-1-yl, 2-buten-2-yl, 1-methyl-1-propen-1-yl,2-methyl-1-propen-1-yl, 1-methyl-2-propen-1-yl, 2-methyl-2-propen-1-yl,1-methyl-1-buten-1-yl, 2-methyl-1-buten-1-yl, 3-methyl-1-buten-1yl,1-methyl-2-buten-1-yl, 2-methyl-2-buten-1-yl, 3-methyl-2-buten-1-yl,1-methyl-3-buten-1-yl, 2-methyl-3-buten-1-yl, 3-methyl-3-buten-1-yl,1-ethyl-1-buten-1-yl, 2-ethyl-1-buten-1-yl, 3-ethyl-1-buten-1-yl,1-ethyl-2-buten-1-yl, 2-ethyl-2-buten-1-yl, 3-ethyl-2-buten-1-yl,1-ethyl-3-buten-1-yl, 2-ethyl-3-buten-1-yl, 3-ethyl-3-buten-1-yl,1,1-dimethyl-1-buten-1-yl, 1,2-dimethyl-1-buten-1-yl,1,3-dimethyl-1-buten-1-yl, 2,2-dimethyl-1-buten-1-yl,3,3-dimethyl-1-buten-1-yl, 1,1-dimethyl-2-buten-1-yl,1,2-dimethyl-2-buten-1-yl, 1,3-dimethyl-2-buten-1-yl,2,2-dimethyl-2-buten-1-yl, 3,3-dimethyl-2-buten-1-yl,1,1-dimethyl-3-buten-1-yl, 1,2-dimethyl-3-buten-1-yl,1,3-dimethyl-3-buten-1-yl, 2,2-dimethyl-3-buten-1-yl and3,3-dimethyl-3-buten-1-yl groups. Still more preferable ones areethenyl, 1-propen-1-yl, 2-propen-1-yl, 3-propen-1-yl, 1-buten-1-yl,1-buten-2-yl, 1-buten-3-yl, 1-buten-4-yl, 2-buten-1-yl, 2-buten-2-yl,1-methyl-1-propen-1-yl, 2-methyl-1-propen-1-yl, 1-methyl-2-propen-1-yl,2-methyl-2-propen-1-yl, 1-methyl-1-buten-1-yl, 2-methyl-1-buten-1-yl,3-methyl-1-buten-1-yl, 1-methyl-2-buten-1-yl, 2-methyl-2-buten-1-yl,3-methyl-2-buten-1-yl, 1-methyl-3-buten-1-yl, 2-methyl-3-buten-1-yl and3-methyl-3-buten-1-yl groups. The most desirable ones are ethenyl,1-propen-1-yl, 2-propen-1-yl, 3-propen-1-yl, 1-buten-1-yl, 1-buten-2-yl,1-buten-3-yl, 1-buten-4-yl, 2-buten-1-yl and 2-buten-2-yl groups.

The term “lower alkynyl group” means a linear or branched C₁₋₆ alkynylgroup which is the residue of a compound having a triple bond in theabove-mentioned alkyl group. Particular examples thereof includeethynyl, 1-propyn-1-yl, 2-propyn-1-yl, 3-propyn-1-yl, 1-butyn-1-yl,1-butyn-2-yl, 1-butyn-3-yl, 1-butyn-4-yl, 2-butyn-1-yl, 2-butyn-2-yl,1-methyl-1-propyn-1-yl, 2-methyl-1-propyn-1-yl, 1-methyl-2-propyn-1-yl,2-methyl-2-propyn-1-yl, 1-methyl-1-butyn-1-yl, 2-methyl-1-butyn-1-yl,3-methyl-1-butyn-1-yl, 1-methyl-2-butyn-1-yl, 2-methyl-2-butyn-1-yl,3-methyl-2-butyn-1-yl, 1-methyl-3-butyn-1-yl, 2-methyl-3-butyn-1-yl,3-methyl-3-butyn-1-yl, 1-ethyl-1-butyn-1-yl, 2-ethyl-1-butyn-1-yl,3-ethyl-1-butyn-1-yl, 1-ethyl-2-butyn-1-yl, 2-ethyl-2-butyn-1-yl,3-ethyl-2-butyn-1-yl, 1ethyl-3-butyn-1-yl, 2-ethyl-3-butyn-1-yl,3-ethyl-3-butyn-1-yl, 1,1dimethyl-1-butyn-1-yl,1,2-dimethyl-1-butyn-1-yl, 1,3-dimethyl-1-butyn-1-yl,2,2-dimethyl-1-butyn-1-yl, 3,3-dimethyl-1-butyn-1-yl,1,1-dimethyl-2-butyn-1-yl, 1,2-dimethyl-2-butyn-1-yl,1,3-dimethyl-2-butyn-1-yl, 2,2-dimethyl-2-butyn-1-yl,3,3-dimethyl-2-butyn-1-yl, 1,1-dimethyl-3-butyn-1-yl,1,2-dimethyl-3-butyn-1-yl, 1,3-dimethyl-3-butyn-1-yl,2,2-dimethyl-3-butyn-1-yl, 3,3-dimethyl-3-butyn-1-yl, 1-pentyn-1-yl,2-pentyn-1-yl, 3-pentyn-1-yl, 4-pentyn-1-yl, 1-pentyn-2-yl,2-pentyn-2-yl, 3-pentyn-2-yl, 4-pentyn-2-yl, 1-pentyn-3-yl,2-pentyn-3-yl, 1-pentyn-1-yl, 2-pentyn-1-yl, 3-pentyn-1-yl,4-pentyn-1-yl, 1-pentyn-2-yl, 2-pentyn-2-yl, 3-pentyn-2-yl,4-pentyn-2-yl, 1-pentyn-3-yl, 2-pentyn-3-yl, 1-methyl-1-pentyn-1-yl,2-methyl-1-pentyn-1-yl, 3-methyl-1-pentyn-1-yl, 4-methyl-1-pentyn-1-yl,1-methyl-2-pentyn-1-yl, 2-methyl-2-pentyn-1-yl, 3-methyl-2-pentyn-1-yl,4-methyl-2-pentyn-1-yl, 1-methyl-3-pentyn-1-yl, 2-methyl-3-pentyn-1-yl,3-methyl-3-pentyn-1-yl, 4-methyl-3-pentyn-1-yl, 1-methyl-4-pentyn-1-yl,2-methyl-4-pentyn-1-yl, 3-methyl-4-pentyn-1-yl, 4-methyl-4-pentyn-1-yl,1-methyl-1-pentyn-2-yl, 2-methyl-1-pentyn-2-yl, 3-methyl-1-pentyn-2-yl,4-methyl-1-pentyn-2-yl, 1-methyl-2-pentyn-2-yl, 2-methyl-2-pentyn-2-yl,3-methyl-2-pentyn-2-yl, 4-methyl-2-pentyn-2-yl, 1-methyl-3-pentyn-2-yl,2-methyl-3-pentyn-2-yl, 3-methyl-3-pentyn-2-yl, 4-methyl-3-pentyn-2-yl,1-methyl-4-pentyn-2-yl, 2-methyl-4-pentyn-2-yl, 3-methyl-4-pentyn-2-yl,4-methyl-4-pentyn-2-yl, 1-methyl-1-pentyn-3-yl, 2-methyl-1-pentyn-3-yl,3-methyl-1-pentyn-3-yl, 4-methyl-1-pentyn-3-yl, 1-methyl-2-pentyn-3-yl,2-methyl-2-pentyn-3-yl, 3-methyl-2-pentyn-3-yl, 4-methyl-2-pentyn-3-yl,1-hexyn-1-yl, 1-hexyn-2-yl, 1-hexyn-3-yl, 1-hexyn-4-yl, 1-hexyn-5-yl,1-hexyn-6-yl, 2-hexyn-1-yl, 2-hexyn-2-yl, 2-hexyn-3-yl, 2-hexyn-4-yl,2-hexyn-5-yl, 2-hexyn-6-yl, 3-hexyn-1-yl, 3-hexyn-2-yl and 3-hexyn-3-ylgroups. Preferable examples thereof include ethynyl, 1-propyn-1-yl,2-propyn-1-yl, 3-propyn-1-yl, 1-butyn-1-yl, 1-butyn-2-yl, 1-butyn-3-yl,1-butyn-4-yl, 2-butyn-1-yl, 2-butyn-2-yl, 1-methyl-1-propyn-1-yl,2-methyl-1-propyn-1-yl, 1-methyl-2-propyn-1-yl, 2-methyl-2-propyn-1-yl,1-methyl-1-butyn-1-yl, 2-methyl-1-butyn-1-yl, 3-methyl-1-butyn-1-yl,1-methyl-2-butyn-1-yl, 2-methyl-2-butyn-1-yl, 3-methyl-2-butyn-1-yl,1-methyl-3-butyn-1-yl, 2-methyl-3-butyn-1-yl, 3-methyl-3-butyn-1-yl,1-ethyl-1-butyn-1-yl, 2-ethyl-1-butyn-1-yl, 3-ethyl-1-butyn-1-yl,1-ethyl-2-butyn-1-yl, 2-ethyl-2-butyn-1-yl, 3-ethyl-2-butyn-1-yl,1-ethyl-3-butyn-1-yl, 2-ethyl-3-butyn-1-yl, 3-ethyl-3-butyn-1-yl,1,1-dimethyl-1-butyn-1-yl, 1,2-dimethyl-1-butyn-1-yl,1,3-dimethyl-1-butyn-1-yl, 2,2-dimethyl-1-butyn-1-yl,3,3-dimethyl-1-butyn-1-yl, 1,1-dimethyl-2-butyn-1-yl,1,2-dimethyl-2-butyn-1-yl, 1,3-dimethyl-2-butyn-1-yl,2,2-dimethyl-2-butyn-1-yl, 3,3-dimethyl-2-butyn-1-yl,1,1-dimethyl-3-butyn-1-yl, 1,2-dimethyl-3-butyn-1-yl,1,3-dimethyl-3-butyn-1-yl, 2,2-dimethyl-3-butyn-1-yl and3,3-dimethyl-3-butyn-1-yl groups. Still preferable ones are ethynyl,1-propyn-1-yl, 2-propyn-1-yl, 3-propyn-1-yl, 1-butyn-1-yl, 1-butyn-2-yl,1-butyn-3-yl, 1-butyn-4-yl, 2-butyn-1-yl, 2-butyn-2-yl,1-methyl-1-propyn-1-yl, 2-methyl-1-propyn-1-yl, 1-methyl-2-propyn-1-yl,2-methyl-2-propyn-1-yl, -methyl-1-butyn-1-yl, 2-methyl-1-butyn-1-yl,3-methyl-1-butyn-1-yl, 1-methyl-2-butyn-1-yl, 2-methyl-2-butyn-1-yl,3-methyl-2-butyn-1-yl, 2-methyl-3-butyn-1-yl, 2-methyl-3-butyn-1-yl and3-methyl-3-butyn-1-yl groups. The most desirable ones are ethynyl,1-propyn-1-yl, 2-propyn-1-yl, 3-propyn-1-yl, 1-butyn-1-yl, 1-butyn-2-yl,1-butyn-3-yl, 1-butyn-4-yl, 2-butyn-1-yl and 2-butyn-2-yl groups.

Examples of the lower cycloalkyl group include cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl groups.

Examples of the lower cycloalkenyl group include cyclopropenyl,cyclobutenyl, cyclopentenyl and cyclohexenyl groups.

The term “C₂₋₆ alkoxy group” means groups corresponding to C₂₋₆ residuesof the above-mentioned lower alkyl groups. Particular examples thereofinclude ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy,t-butoxy, n-pentyloxy, i-pentyloxy, sec-pentyloxy, t-pentyloxy,neopentyloxy, 1-methylbutoxy, 2-methylbutoxy, 1,1-dimethylpropoxy,1,2-dimethylpropoxy, n-hexyloxy, i-hexyloxy, 1-methylpentyloxy,2-methylpentyloxy, 3-methylpentyloxy, 1,1-dimethylbutoxy,1,2-dimethylbutoxy, 2,2-dimethylbutoxy, 1,3-dimethylbutoxy,2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy,1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxyand 1-ethyl-2-methylpropoxy groups. Preferable examples thereof includeethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, t-butoxy,n-pentyloxy, i-pentyloxy, sec-pentyloxy, t-pentyloxy, neopentyloxy,1-methylbutoxy, 2-methylbutoxy, 1,1-dimethylpropoxy,1,2-dimethylpropoxy, n-hexyloxy and i-hexyloxy groups. Still morepreferable examples are ethoxy, n-propoxy, i-propoxy, n-butoxy,i-butoxy, sec-butoxy and t-butoxy groups.

The term “lower alkylene group” in the definition of X and Y means adivalent group formed by eliminating one hydrogen atom from each of thecarbon atoms at both ends of a linear saturated C₁₋₆ hydrocarbon.Particular examples thereof include methylene, ethylene, propylene,butylene, pentylene and hexylene groups. Preferable examples thereofinclude methylene, ethylene, propylene, butylene and pentylene groups.Methylene, ethylene, propylene and butylene groups are still morepreferable and methylene, ethylene and propylene groups are furtherpreferable therefor. Among them all, a methylene group is the mostdesirable.

Similarly, the term “lower alkenylene group” means a divalent groupformed by eliminating one hydrogen atom from each of the carbon atoms atboth ends of a linear unsaturated C₂₋₆ hydrocarbon. Particular examplesthereof include vinylene, propenylene, butenylene, pentenylene andhexenylene groups. Preferable examples thereof include vinylene,propenylene, butenylene and pentenylene groups and vinylene, propenyleneand butenylene groups are still preferable. Vinylene and propenylenegroups are more preferable and a vinylene group is the most desirable.

Similarly, the term “lower alkynylene group” means a divalent groupformed by eliminating one hydrogen atom from each of the carbon atoms atboth ends of a linear unsaturated C₂₋₆ hydrocarbon. Particular examplesthereof include ethynyl, propynyl, butynyl, pentynyl and hexynyl groups.Preferable examples thereof include ethynyl, propynyl, butynyl andpentynyl groups. Ethynyl, propynyl and, butynyl groups are still morepreferable and ethynyl and propynyl groups are further preferabletherefor. An ethynyl group is the most desirable.

l and m may be the same or different and each represents 0 or 1.

The fact that l is 0 means a compound of the following formula whereinthe ring A is bonded not via “optionally substituted lower alkyleneoptionally having a heteroatom, optionally substituted lower alkenyleneoptionally having a heteroatom or optionally substituted loweralkynylene optionally having a heteroatom” represented by X butdirectly:

wherein Y, m and the rings A and B are each as defined above.

Similarly, the fact that m is 0 means a compound of the followingformula wherein the bridgehead carbon atom of the ring A is bonded notvia “optionally substituted lower alkylene optionally having aheteroatom, optionally substituted lower alkenylene optionally having aheteroatom or optionally substituted lower alkynylene optionally havinga heteroatom” represented by Y but directly to the bridgehead carbonatom of the ring B:

wherein X, l and the rings A and B are each as defined above.

Therefore, the fact that l and m are the same and each represents 0means a compound of the following formula wherein the ring A is bondednot via “optionally substituted lower alkylene optionally having aheteroatom, optionally substituted lower alkenylene optionally having aheteroatom or optionally substituted lower alkynylene optionally havinga heteroatom” represented by X but directly and the bridgehead carbonatom of the ring A is bonded not via “optionally substituted loweralkylene optionally having a heteroatom, optionally substituted loweralkenylene optionally having a heteroatom or optionally substitutedlower alkynylene optionally having a heteroatom” represented by Y butdirectly to the bridgehead carbon atom of the ring B.

wherein the rings A and B are each as defined above.

The ring A represents an optionally substituted cycloalkyl ringoptionally having one or more heteroatoms.

The term “heteroatom” as used herein means in particular oxygen, sulfur,nitrogen, phosphorus, arsenic, antimony, silicon, germanium, tin, lead,boron, mercury, etc. Preferable examples thereof include oxygen, sulfurand nitrogen atoms and a nitrogen atom is Still more preferable.

In the expression “having a heteroatom” or “optionally having aheteroatom” as used herein, the heteroatom has the meaning as definedabove.

A cycloalkyl ring means a saturated monocyclic hydrocarbon. Namely,particular examples of the ring A are those represented by the followingstructural formulae optionally having a substituent and optionallyhaving one or more heteroatoms:

Preferable examples thereof include those represented by the followingstructural formulae optionally having a substituent and optionallyhaving one or more heteroatoms:

Still more preferable examples thereof include those represented by thefollowing structural formulae optionally having a substituent andoptionally having one or more heteroatoms:

Still more preferable examples thereof include those represented by thefollowing structural formula optionally having a substituent andoptionally having one or more heteroatoms:

The most desirable one is an optionally substituted piperidine ringoptionally having one or more heteroatoms.

The ring B represents a ring optionally having one or more double bondsin the ring selected from the following ones: a) an optionallysubstituted cycloalkyl ring optionally having a heteroatom; b) anoptionally substituted bicycloalkyl ring optionally having a heteroatomwherein the different atoms (bridgehead carbon atoms) in the ring B arebonded to each other via an optionally substituted C₁ or higher alkylenegroup optionally having a heteroatom; and c) an optionally substitutedspiro-hydrocarbon ring optionally having a heteroatom wherein both endsof an optionally substituted C₁ or higher alkylene group optionallyhaving a heteroatom are bonded to a carbon atom (bridgehead carbon atom)in the ring B. Thus, particular examples of the ring B are thoserepresented by the following structural formulae optionally having oneor more double bond in the ring, optionally having a substituent andoptionally having a heteroatom:

Preferable examples thereof include those represented by the followingstructural formulae optionally having a substituent and optionallyhaving a heteroatom:

Still more preferable examples thereof include those represented by thefollowing structural formulae optionally having a substituent andoptionally having a heteroatom:

Still more preferable examples thereof include those represented by thefollowing structural formulae optionally having a substituent andoptionally having a heteroatom:

Particularly preferable examples thereof include those represented bythe following structural formulae optionally having a substituent andoptionally having a heteroatom:

The most desirable ones are those represented by the followingstructural formulae optionally having a substituent and optionallyhaving a heteroatom:

X¹ represents an optionally substituted lower alkylene optionally havinga heteroatom, optionally substituted lower alkenylene optionally havinga heteroatom or optionally substituted lower alkynylene optionallyhaving a heteroatom. Thus, it has the same meaning as that of X asdefined above. The heteroatom in the definition of X¹ is preferably anitrogen atom, though it is not restricted thereto.

l¹ is 0 or 1.

When l¹ is 0, therefore, the following formula:

wherein X, l¹ and the ring A¹ are each as defined above;

means the following formula:

wherein the ring A¹ is as defined above.

The ring A¹ represents: a) an optionally substituted cycloalkyl ringoptionally having one or more heteroatoms; b) an optionally substitutedcycloalkenyl ring optionally having one or more heteroatoms; or c) anoptionally substituted spiro-hydrocarbon ring optionally having aheteroatom, wherein both ends of an optionally substituted C₁or higheralkylene group optionally having a heteroatom are bonded to a carbonatom (bridgehead carbon atom) in the ring A¹. Thus, particular examplesof the ring A¹ include those represented by the following structuralformulae optionally having a substituent, optionally having a heteroatomand optionally having a double bond in the ring:

Preferable examples thereof include those represented by the followingstructural formulae optionally having a substituent, optionally having aheteroatom and optionally having a double bond in the ring:

Still more preferable examples thereof include those represented by thefollowing structural formulae optionally having a substituent,optionally having a heteroatom and optionally having a double bond inthe ring:

Still more preferable examples thereof include those represented by thefollowing structural formulae optionally having a substituent,optionally having a heteroatom and optionally having a double bond inthe ring:

Particularly preferable examples thereof include those represented bythe following structural formulae optionally having a substituent,optionally having a heteroatom and optionally having a double bond inthe ring:

The most desirable examples thereof are those represented by thefollowing structural formulae optionally having a substituent,optionally having a heteroatom and optionally having a double bond inthe ring:

and piperidine and pyrrolidine rings optionally having a substituent,optionally having a heteroatom and optionally having a double bond inthe ring.

X² represents an optionally substituted lower alkylene optionally havinga heteroatom, optionally substituted lower alkenylene optionally havinga heteroatom or optionally substituted lower alkynylene optionallyhaving a heteroatom.

l² is 0 or 1.

When l² is 0, therefore, the following formula:

—(X²)₁2—Q

wherein X², l² and Q are each as defined above;

means the following formula:

—Q

wherein Q is as defined above.

Q is as defined above. In the definition of Q, particular examples of a)heteroaryl consisting of one or more optionally substituted ringsinclude rings represented by the following structural formulaeoptionally having a substituent:

Preferable examples are those represented by the following structuralformulae:

Still more preferable examples are those represented by the followingstructural formulae:

Still further preferable examples are those represented by the followingstructural formulae:

Particularly preferable examples are those represented by the followingstructural formulae:

The most desirable ones are those represented by the followingstructural formulae:

Particular examples of aryl consisting of one or more optionallysubstituted rings include phenyl, tolyl, xylyl, cumenyl, mesityl andnaphthyl groups.

The expression “b) optionally substituted quaternary ammonio” meansthose having optionally substituted tetravalent nitrogen. Such aquaternary ammonio group may be an acyclic one, a cyclic one or acombination thereof. It may have one or more heteroatoms selected fromamong nitrogen, sulfur and oxygen. Examples of the acyclic quaternaryammonio group include those represented by the following formula:

wherein R²³ to R²⁵ may be the same or different and each representslower alkyl, lower alkoxy(lower alkyl), hydroxy(lower alkyl),carboxy(lower alkyl), amino(lower alkyl), carbamoyl(lower alkyl), loweralkenyl, lower alkynyl, halogeno(lower alkyl), halogeno(lower alkenyl),halogeno(lower alkynyl) or aryl. Particular examples thereof includethose represented by the following formulae optionally having asubstituent:

wherein Me represents methyl; Et represents ethyl; Pr represents propyl;and Bu represents butyl; the same will apply hereinafter.

Preferable examples thereof include those represented by the followingformulae optionally having a substituent:

Still more preferable examples thereof include those represented by thefollowing formulae optionally having a substituent:

The most preferable examples thereof are those represented by thefollowing formulae:

Examples of the cyclic quaternary ammonio group include thoserepresented by the following formula:

wherein R²⁶ represents lower alkyl, lower alkoxy(lower alkyl),hydroxy(lower alkyl), carboxy(lower alkyl), amino(lower alkyl),carbamoyl(lower alkyl), lower alkenyl, lower alkynyl, halogeno(loweralkyl), halogeno(lower alkenyl), halogeno(lower alkynyl) or aryl; andthe ring A⁴ represents an optionally substituted cycloalkyl ringoptionally having a double bond in the ring;

those represented by the following formula:

wherein R²⁷ represents lower alkyl, lower alkoxy(lower alkyl),hydroxy(lower alkyl), carboxy(lower alkyl), amino(lower alkyl),carbamoyl(lower alkyl), lower alkenyl, lower alkynyl, halogeno(loweralkyl), halogeno(lower alkenyl), halogeno(lower alkynyl) or aryl; andthe ring A⁵ represents an optionally substituted heteroaryl ringoptionally having one or more heteroatoms;

or those represented by the following formula:

wherein the ring A⁶ represents an optionally substituted heteroaryl ringoptionally having one or more heteroatoms.

Particular examples thereof include those represented by the followingstructural formulae optionally having a substituent and optionallyhaving one or more heteroatoms:

wherein R²⁶ and R²⁷ are each as defined above.

Preferable examples thereof include those represented by the followingstructural formulae optionally having a substituent and optionallyhaving one or more heteroatoms:

wherein R²⁶ and R²⁷ are each as defined above.

Still more preferable examples thereof include those represented by thefollowing structural formulae optionally having a substituent andoptionally having one or more heteroatoms:

wherein R²⁶ is as defined above.

Still more preferable examples thereof include those represented by thefollowing structural formulae optionally having a substituent andoptionally having one or more heteroatoms:

wherein R²⁶ is as defined above.

Particularly preferable examples thereof include those represented bythe following structural formulae optionally having a substituent andoptionally having one or more heteroatoms:

wherein R²⁶ is as defined above.

The most desirable ones are those represented by the followingstructural formulae optionally having a substituent and optionallyhaving one or more heteroatoms:

wherein R²⁶ is as defined above.

R⁵ and R⁶ may be the same or different and each represents hydrogen orlower alkyl. The term “lower alkyl” as used herein has the same meaningas the one defined above.

Thus, particular examples of c) the group represented by the followingformula:

wherein R⁵ and R⁶ are each as defined above, include those representedby the following structural formulae:

Preferable examples thereof include those represented by the followingstructural formulae:

Still more preferable examples thereof include those represented by thefollowing structural formulae:

The most desirable ones are those represented by the followingstructural formulae:

Particular examples of the lower acyl group include formyl, acetyl,propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl,acryloyl, methacryloyl, crotonyl, chloroformyl, pyruvoyl, oxalo,methoxalyl, ethoxalyl and benzoyl groups.

The lower acyloxy group means those corresponding to the above-mentionedlower acyl groups. Particular examples thereof include formyloxy,acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy,isovaleryloxy, pivaloyloxy, hexanoyloxy, acryloyloxy, methacryloyloxy,crotonyloxy, chloroformyloxy, pyruvoyloxy, oxaloxy, methoxalyloxy,ethoxalyloxy and benzoyloxy groups.

R⁷ and R⁸ are each as defined above. In the definition of R⁷ and R⁸, thelower alkyl and lower cycloalkyl groups are each as defined above.

Also, the lower alkyl groups in the definition of R⁷¹, R⁷², R⁷³, R⁷⁴,R⁷⁵, R⁷⁶, R⁷⁷ and R⁸¹ and the lower cycloalkyl groups in the definitionof R⁷² and R⁷³ have each the same meaning as the one defined above.

The aryl groups in the definition of R⁷¹, R⁷², R⁷³, R⁸¹, R⁸³, R⁸⁴ andR⁸⁵ means aromatic ring groups. Particular examples thereof includephenyl, tolyl, xylyl, cumenyl, mesityl and naphthyl groups.

The amino protecting group is not restricted but may be an arbitrary oneknown as an amino protecting group in organic synthesis. Examplesthereof include optionally substituted lower alkanoyl groups such asformyl, acetyl, chloroacetyl, dichloroacetyl, propionyl, phenylacetyl,phenoxyacetyl and thienylacetyl groups; optionally substituted loweralkoxycarbonyl groups such as benzyloxycarbonyl, t-butoxycarbonyl andp-nitrobenzyloxycarbonyl groups; substituted lower alkyl groups such asmethyl, t-butyl, 2,2,2-trichloroethyl, trityl, p-methoxybenzyl,p-nitrobenzyl, diphenylmethyl, pivaloyloxymethyl, methoxymethyl andethoxymethyl groups; substituted silyl groups such as trimethylsilyl andt-butyldimethylsilyl groups; substituted silylalkoxyalkyl groups such astrimethylsilylmethoxymethyl, trimethylsilylethoxymethyl,t-butyldimethylsilylmethoxymethyl and t-butyldimethylsilylethoxymethylgroups; and optionally substituted benzylidene groups such asbenzylidene, salicylidene, p-nitrobenzylidenei m-chlorobenzylidene,3,5-di(t-butyl)-4-hydroxybenzylidene and 3,5-di(t-butyl)benzylidenegroups.

Such a protective group can be eliminated by conventional methods suchas hydrolysis or reduction selected depending on the type thereof.

The term “protected hydroxy” means a hydroxyl group protected by ahydroxyl protecting group. Examples thereof are not restricted, so longas they are protected by protecting groups commonly known as a hydroxylprotecting group in organic synthesis. Examples of the hydroxylprotecting group include lower alkylsilyl groups such as trimethylsilyland t-butyldimethylsilyl groups; lower alkoxymethyl groups such asmethoxymethyl and 2-methoxymethyl groups; a tetrahydropyranyl group;aralkyl groups such as benzyl, p-methoxybenzyl, 2,4-dimethoxybenzyl,o-nitrobenzyl, p-nitrobenzyl and trityl groups; acyl groups such asformyl and acetyl groups; lower alkoxycarbonyl groups such ast-butoxycarbonyl, 2-iodoethoxycarbonyl and 2,2,2-trichloroethoxycarbonylgroups; alkenyloxycarbonyl groups such as 2-propenyloxycarbonyl,2-chloro-2-propenyloxycarbonyl, 3-methoxycarbonyl-2-propenyloxycarbonyl,2-methyl-2-propenyloxycarbonyl, 2-butenyloxycarbonyl andcinnamyloxycarbonyl groups; and aralkyloxycarbonyl groups such asbenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyland p-nitrobenzyloxycarbonyl groups.

R⁸² represents hydrogen, lower alkyl or a mercapto protective group. Thelower alkyl as used herein has the same meaning as the one definedabove. The mercapto protective group may be an arbitrary one withoutrestriction so long as it is commonly known as a mercapto protectivegroup in organic synthesis. More particularly speaking, use can be madeof the above-mentioned hydroxy protective groups or disulfidederivatives as the mercapto protective group.

The term “protected carboxy” means a carboxyl group protected by acarboxyl protecting group. The carboxyl protective group may be anarbitrary one without restriction so long as it is commonly known as acarboxyl protecting group in organic synthesis. Particular examples ofthe carboxyl protective group include linear and branched C₁₋₄ loweralkyl groups such as methyl, ethyl, isopropyl and t-butyl groups;halogeno(lower alkyl) groups such as 2-iodoethyl and2,2,2-trichloroethyl groups; lower alkoxymethyl groups such asmethoxymethyl, ethoxymethyl and isobutoxymethyl groups; lower aliphaticacyloxymethyl groups such as butyryloxymethyl and pivaloyloxymethylgroups; 1-(lower alkoxy)carbonyloxyethyl groups such as1-methoxycarbonyloxyethyl and 1-ethoxycarbonyloxyethyl groups; aralkylgroups such as benzyl, p-methoxybenzyl, o-nitrobenzyl and p-nitrobenzylgroups; and benzhydryl and phthalidyl groups.

W represents oxygen or sulfur. When W is oxygen, therefore, the grouprepresented by the following formula:

wherein W, R⁸³ and R⁸⁴ are each as defined above,

represents a group represented by the following formula:

wherein W, R⁸³ and R⁸⁴ are each as defined above.

When W is sulfur, therefore, the group represented by the followingformula:

wherein W, R⁸³ and R⁸⁴ are each as defined above,

represents a group represented by the following formula:

wherein W, R⁸³ and R⁸⁴ are each as defined above.

R⁸³ and R⁸⁴ may be the same or different and each represents hydrogen,lower alkyl, lower cycloalkyl, cyano or a group represented by thefollowing formula:

—SO₂R⁸⁵

wherein R⁸⁵ represents hydrogen, hydroxy or lower alkyl.

Alternatively, R⁸³ and R⁸⁴ together form an optionally substituted lowercycloalkyl optionally having one or more heteroatoms.

The lower alkyl groups in R⁸³, R⁸⁴ and R⁸⁵ and the lower cycloalkylgroups in R⁸³ and R⁸⁴ are each as defined above.

Particular examples of the optionally substituted lower cycloalkyloptionally having one or more heteroatoms formed by R⁸³ and R⁸⁴ togetherinclude optionally substituted pyrrolidyl, imidazolidyl, piperazolidyl,piperidyl, piperazyl and morpholino groups optionally having one or moreheteroatoms.

R⁸⁶, R⁸⁷ and R⁸⁸ are as defined above. Also, the lower alkyl groups inR⁸⁶, R⁸⁷ and R⁸⁸ have the same meaning as the one defined above. Theterm “hydroxy(lower alkyl)” means a lower alkyl group substituted withhydroxy. The optionally substituted lower cycloalkyl group optionallyhaving one or more heteroatoms formed by R⁸⁶ and R⁸⁷ together has thesame meaning as the one defined above with respect to R⁸³ and R⁸⁴.

R⁹⁰ and R⁹¹ each represents hydrogen or lower alkyl. The lower alkyl hasthe same meaning as the one defined above.

Next, the definition of R will be illustrated.

R is as defined above and the lower alkyl groups in the definition of Ralso have the same meaning as the one defined above.

The term “optionally substituted arylalkyl” means an optionallysubstituted alkyl group substituted by an optionally substituted arylgroup. Particular examples of the aryl group include benzene, pentalene,indene, naphthalene, azulene, heptalene, biphenylene, indacene,acenaphthylene, fluorene, phenalene, phenanthrene and anthracene.Preferable examples thereof include benzene, pentalene, indene,naphthalene and azulene. Particular examples of the alkyl group includethe optionally substituted lower alkyl groups as cited above.

The term “optionally substituted heteroarylalkyl” means an optionallysubstituted alkyl group substituted by an optionally substitutedheteroaryl group. Particular examples of the heteroaryl group includepyridine, thiophene, furan, pyrrole, oxazole, isoxazole, thiazole,isothiazole, imidazole, triazole, pyrazole, furazan, thiadiazole,oxadiazole, pyridazine, pyrimidine, pyrazine, indole, isoindole,indazole, chromene, quinoline, isoquinoline, cinnoline, quinazoline,quinoxaline, naphthyridine, phthalazine, purine, pteridine, thienofuran,imidazothiazole, benzofuran, benzothiophene, benzoxazole, benzothiazole,benzothiadiazole, benzimidazole, imidazopyridine, pyrrolopyridine,pyrrolopyrimidine and pyridopyrimidine. Preferable examples thereofinclude pyridine, thiophene, thiazole, thiadiazole, imidazole,pyrimidine, benzimidazole, imidazopyridine and purine. Particularexamples of the alkyl group include the optionally substituted loweralkyl groups as cited above.

The amino protecting group is as defined above.

The lower alkylene, lower alkenylene and lower alkynylene groups in X³are each as defined above.

The lower alkyl group and the amino protecting group in R⁹ and R¹⁰ areeach as defined above.

The lower alkylene, lower alkenylene and lower alkynylene groups in X⁴are each as defined above.

The lower alkyl group and the carboxy protecting group in R¹¹ are eachas defined above.

Next, the definition of E will be illustrated.

E is as defined above and R⁴ in the definition of E also has the samemeaning as the one described with respect to R¹ to R³.

Next, the definition of Z will be illustrated.

Z is as defined above and the lower alkyl group and the amino protectivegroup in R¹² in the definition of Z also have each the same meaning asthe one defined above.

Next, the definition of the ring G will be illustrated.

The ring G represents an optionally substituted heteroaryl ring havingone or more nitrogen atoms. Particular examples of the heteroaryl grouphaving one or more nitrogen atoms include pyridine, pyrrole, oxazole,isoxazole, thiazole, isothiazole, imidazole, triazole, pyrazole,furazan, thiadiazole, oxadiazole, pyridazine, pyrimidine, pyrazine,indole, isoindole, indazole, quinoline, isoquinoline, cinnoline,quinazoline, quinoxaline, naphthyridine, phthalazine, purine, pteridine,imidazothiazole, benzoxazole, benzothiazole, benzothiadiazole,benzimidazole, imidazopyridine, pyrrolopyridine, pyrrolopyrimidine andpyridopyrimidine. Preferable examples thereof include pyridine, pyrrole,oxazole, isoxazole, thiazole, isothiazole, imidazole, triazole,pyrazole, furazan, thiadiazole, oxadiazole, pyridazine, pyrimidine andpyridine. Particularly preferable examples thereof include pyridine,pyrrole, imidazole, triazole, pyrazole, pyridazine, pyrimidine andpyrazine. Still preferable examples are imidazole, triazole, pyridazine,pyrimidine and pyrazine. Particularly preferable ones are pyridine,pyridazine, pyrimidine and pyrazine. The most desirable ones arepyrimidine and pyrazine.

Thus the compounds represented by the formula (I) have been defined,provided that the benzopiperidine derivatives as will be specified beloware excluded from the present invention: a) that in which R¹ to R³ areeach hydrogen, E is CH, Z is O, S, or SO₂ and the ring G is anunsubstituted (i.e., all of the substituents being hydrogen atoms)heteroaryl ring having one or more nitrogen atoms; b) that in which R¹to R³ are each hydrogen, E is CH, Z is O, S, SO₂ or NH and thesubstituent(s) of the ring G is optionally substituted phenyl,pyridinyl, thienyl, nitro, cyano, halogeno, acetyl, methyl, ethyl,t-butyl, ethoxy, N-methylpiperazyl, naphthyl, optionally protectedcarboxyalkyl or amino; c) that in which R¹ to R³ are each hydrogen, E isCH, Z is NH and the ring G is unsubstituted (i.e., all of thesubstituents being hydrogen atoms) pyridazine; and d) that in which R¹to R³ are each hydrogen, E is CH, R is a group other than hydrogen, Z isNR^(12′) (R^(12′) being lower alkyl or an amino protective group) andthe ring G is an optionally substituted heteroaryl ring optionallyhaving one or more nitrogen atoms. The term “optionally substitutedphenyl” as used herein means a phenyl group optionally substituted bymethoxy or halogeno. The term “optionally protected carboxyalkyl” meansa carboxyalkyl group which may have a protecting group commonly employedas a carboxy protecting group in organic synthesis.

In particular, benzopiperidine derivatives of the formula (I) wherein Zis S, their salts or hydrates thereof are useful.

In particular, benzopiperidine derivatives of the formula (I) whereinthe ring G is an optionally substituted pyrazine ring, their salts orhydrates thereof are useful.

In particular, benzopiperidine derivatives of the formula (I) wherein Zis S and the ring G is an optionally substituted pyrazine ring, theirsalts or hydrates thereof are useful.

In the definition of the compounds represented by the above formula(II), R, Z, E and the ring G have each the same meaning as the onedefined above. Now, the definition of U will be illustrated.

U is as defined above and X, Y, l, m, the rings A and B, X¹, l¹ and thering A¹ employed in the definition of U also have each the same meaningas the one defined with respect to the formula (I).

In the definition of the compounds represented by the above formula(III), R, Z, E and the ring G have each the same meaning as the onedefined above. Now, the definition of U¹ will be illustrated.

U¹ is as defined above and X, Y, l, m, the rings A and B, X¹, l¹ and thering A¹ employed in the definition of U¹ also have each the same meaningas the one defined with respect to the formula (I).

In the present invention, the type of salt is not particularlyrestricted. Examples thereof include inorganic acid addition salts suchas hydrofluoride, hydrochloride, sulfate, nitrate, perchlorate,phosphate, carbonate, bicarbonate, hydrobromide and hydriodide; organiccarboxylic acid addition salts such as acetate, maleate, fumarate,oxalate, lactate, tartrate and trifluoroacetate; organic sulfonic acidaddition salts such as methanesulfonate, trifluoromethanesulfonate,ethanesulfonate, hydroxymethanesulfonate, hydroxyethanesulfonate,benzenesulfonate, toluenesulfonate and taurine salt; amine additionsalts such as trimethylamine salt, triethylamine salt, pyridine salt,procaine salt, picoline salt, dicyclohexylamine salt,N,N′-dibenzylethylenediamine salt, N-methylglucamine salt,diethanolamine salt, triethanolamine salt,tris(hydroxymethylamino)methane salt and phenethylbenzylamine salt;alkali metal addition salts such as sodium salt and potassium salt;alkaline earth metal addition salts such as magnesium salt and calciumsalt; and amino acid addition salts such as argininate, lysinate,serinate, glycinate, aspartate and glutamate.

The compounds of the present invention are benzopiperidine derivativesrepresented by the above formula (I), their salts or hydrates thereof.Preferable ones are the above compounds wherein at least one of R¹ to R³is a group represented by the following formula while other group(s) arehydrogen, their salts and hydrates thereof:

wherein X, Y, l, m and the rings A and B are each as defined above.

Still more preferable ones are benzopiperidine derivatives representedby the above formula (II), their salts or hydrates thereof. Stillpreferable ones are benzopiperidine derivatives represented by the aboveformula (III), their salts or hydrates thereof. Particularly preferableones are those wherein Z is S and, still more preferably, the ring G ispyrazine, their salts or hydrates thereof. The most desirable ones arebenzopiperidine derivatives represented by the following formula, theirsalts or hydrates thereof:

Among all, 10H-pyrazino[2,3-b][1,4]bentothiazine derivatives representedby the following formula are particularly preferable:

wherein R¹ to R⁴ are each as defined above.

Moreover, the benzopiperidine derivatives represented by the aboveformula (I), i.e., the compounds of the present invention, theirpharmacologically acceptable salts or hydrates thereof are useful as adrug.

Particularly preferable drugs containing these benzopiperidinederivatives represented by the above formula (I), theirpharmacologically acceptable salts or hydrates thereof are preventivesand remedies for inflammatory diseases or autoimmune diseases, moreparticularly inflammatory immune diseases, for example, asthma,nephritis, ischemic reflow disorders, psoriasis, atopic dermatitis andthe rejection reaction accompanying organ transplantation and autoimmunediseases such as arthritis and collagen disease. Still more preferabledrugs are preventives and remedies for arthritis which contain thebenzopiperidine derivatives represented by the above formula (I), theirsalts or hydrates thereof.

In addition, it is highly worthwhile to use the benzopiperidinederivatives represented by the above formula (I), their salts orhydrates thereof in the production of drugs and to use thebenzo-piperidine derivatives represented by the above formula (I), theirsalts or hydrates thereof in the treatment of immune diseases.Furthermore, the benzopiperidine derivatives represented by the aboveformula (I), their salts or hydrates thereof are highly useful asremedies ensuring the efficacious administration of these compounds.

The dose of the drugs according to the present invention variesdepending on the severity of the symptoms, the age, sex and body weightof the patient, the administration method, the disease, etc. In usual,such a drug may be administered in a daily dose of 10 μg to 50 g to anadult one to several times per day.

The drugs according to the present invention may be administered by anarbitrary method without restriction. Namely, they can be orally orparenterally administered in a conventional manner.

To produce pharmaceutical preparations thereof, use can be made offillers, binders, lubricants, coloring agents, corrigents, etc. commonlyemployed in the art optionally together with stabilizers, emulsifiers,sorbefacients, surfactants, etc. These preparations are produced byblending components commonly employed in pharmaceutical preparations ina conventional manner.

Examples of these components include animal and vegetable oils (soybeanoil, beef tallow, synthetic glycerides, etc.), hydrocarbons (liquidparaffin, squalane, solid paraffin, etc.), ester oils (octyldodecylmyristate, isopropyl myristate, etc.), higher alcohols (cetostearylalcohol, behenyl alcohol, etc.), silicone resins, silicone oils,surfactants (polyoxyethylene fatty acid esters, sorbitan fatty acidesters, glycerol fatty acid esters, polyoxyethylene sorbitan fatty acidesters, polyoxyethylene-hardened castor oil,polyoxyethylene/polyoxypropylene block copolymer, etc.), water-solublepolymers (hydroxyethylcellulose, polyacrylic acid, carboxyvinyl polymer,polyethylene glycol, polyvinylpyrrolidone, methylcellulose, etc.),alcohols (ethanol, isopropanol, etc.), polyhydric alcohols (glycerol,propylene glycol, dipropylene glycol, sorbitol, etc.), saccharides(glucose, sucrose, etc.), inorganic powders (silicic acid anhydride,aluminum magnesium silicate, aluminum silicate, etc.) and purifiedwater. To regulate the pH value, use can be made of inorganic acids(hydrochloric acid, phosphoric acid, etc.), alkali metal salts ofinorganic acids (sodium phosphate, etc.), inorganic bases (sodiumhydroxide, etc.), organic acids (lower fatty acids, citric acid, lacticacid, etc.), metal salts of organic acids (sodium citrate, sodiumlactate, etc.) and organic bases (arginine, ethanolamine, etc.). Ifneeded, preservatives, antioxidants, etc. may be further added thereto.

The pharmacologically acceptable salts are not particularly restrictedin type. Examples thereof include inorganic acid addition salts such ashydrochloride, sulfate, carbonate, bicarbonate, hydrobromide andhydriodide; organic carboxylic acid addition salts such as acetate,maleate, lactate, tartrate and trifluoroacetate; organic sulfonic acidaddition salts such as methanesulfonate, hydroxymethanesulfonate,hydroxyethanesulfonate, benzenesulfonate, toluenesulfonate and taurinesalt; amine addition salts such as trimethylamine salt, triethylaminesalt, pyridine salt, procaine salt, picoline salt, dicyclohexylaminesalt, N,N′-dibenzylethylenediamine salt, N-methylglucamine salt,diethanolamine salt, triethanolamine salt,tris(hydroxymethylamino)methane salt and phenethylbenzylamine salt; andamino acid addition salts such as argininate, lysinate, serinate,glycinate, aspartate and glutamate.

The compounds of the present invention can be produced by, for example,the following method. Namely, a compound represented by the formula (IV)or (IV′):

wherein R, E, Z, the ring G, X and l are each as defined above, and Lev.represents a leaving group,

is reacted with a compound represented by the formula (V):

wherein Y, m and the rings A² and B are each as defined above, and thering B is optionally protected,

followed by, if required, deblocking and thus a benzopiperidinederivative represented by the formula (VI), its salt or hydrates thereofcan be produced:

wherein R, E, Z, the ring G, X, Y, l, m and the rings A² and B are eachas defined above.

In the production of the compounds of the present invention, therefore,10H-pyrazino[2,3-b][1,4]benzothiazine derivatives represented by thefollowing formula (IV-1) or (IV′-1), their salts or hydrates thereof:

wherein Lev. is as defined above, and bicycloalkyl derivativesrepresented by the following formula (VII), their salts or hydratesthereof:

wherein Y, m, the rings A² and B are each as defined above, R¹³represents hydrogen, lower alkyl or an amino protective group, and R¹⁴and R¹⁵ may be the same or different and each represents hydrogen orlower alkyl, are useful as the production intermediates.

The term “Lev.” as used herein means a leaving group which may be anarbitrary one commonly known as a leaving group in organic synthesiswithout restriction. Examples thereof include halogen atoms such aschlorine, bromine and iodine atoms; alkylthio groups such as methylthio,ethylthio and propylthio groups; arylthio groups such as phenylthio,toluylthio and 2-pyridylthio groups; alkylsulfonyloxy groups such asmethanesulfonyloxy, trifluoromethanesulfonyloxy, ethanesulfonyloxy andpropanesulfonyloxy groups; arylsulfonyloxy groups such asbenzenesulfonyloxy and p-toluenesulfonyloxy groups; alkanoyloxy groupssuch as acetoxy and trifluoroacetoxy groups; alkoxy groups such asmethoxy, ethoxy and propoxy groups; alkylamino groups such asmethylamino, ethylamino, propylamino and butylamino groups; dialkylaminogroups such as dimethylamino, diethylamino, dipropylamino,methylethylamino, ethylpropylamino and methylpropylamino groups; andsubstituted phosphoryloxy groups such as a diphenoxyphosphoryloxy group.

In the formula (VII), the lower alkyl and the amino protective group inthe definition of R¹³ have each the same meaning as the one definedabove. Similarly, the lower alkyl in R¹⁴ and R¹⁵ has the same meaning asthe one defined above. Also, Y, m and the rings A² and B are each asdefined above.

Among the intermediates represented by the formula (VII) in theproduction of the compounds of the present invention, bicycloalkylderivatives represented by the following formula (X), their salts andhydrates thereof are useful:

wherein Y, m, the rings A² and B and R¹³ are each as defined above; X⁵represents an optionally substituted lower alkylene optionally having aheteroatom, optionally substituted lower alkenylene optionally having aheteroatom or optionally substituted lower alkynylene optionally havinga heteroatom; l⁵ is 0 or 1; and Q¹ represents carboxy, alkoxycarbonyl,sulfamoyl, amido, optionally protected hydroxy or optionally protectedamino.

In particular, bicycloalkyl derivatives represented by the followingformula (XI), (XII), (XIII), (XIV), (XV) or (XVI), their salts andhydrates thereof are useful:

wherein R¹³, X⁵, l⁵ and Q¹ are each as defined above; and R^(14′) andR^(15′) may be the same or different and each represents hydrogen orlower alkyl, provided that the following cases are excluded: that inwhich, in the formula (XI) or (XII), R^(15′) and R^(14′) are eachhydrogen, l⁵ is 0 and Q¹ is carboxy or ethoxycarbonyl; that in which, inthe formula (XI), R¹³ is methyl, l⁵ is 1, X⁵ has one carbon atom andforms a double bond with a carbon on the ring bonded thereto and Q¹ isethoxycarbonyl, 4-methoxy-phenylcarbonyl or formyl, or R¹³ is methyl, l⁵is 1, X⁵ is unsubstituted methylene and Q¹ is ethoxycarbonyl; and thatin which, in the formula (XIII), R¹³ is benzyl or benzoyl, l⁵ is 0 andQ¹ is ethoxycarbonyl.

Further, bicycloalkyl derivatives selected from among compoundsrepresented by the following formulae 1) to 3), their salts and hydratesthereof are still more useful:

wherein R¹³is as defined above; and R¹⁸ represents hydrogen, lower alkylor a carboxy protecting group, provided that the case where, in acompound of formula 1), R¹³ is methyl and R¹⁸ is ethyl is excluded. Thelower alkyl and the amino protecting group in the definition of R¹³ haveeach the same meaning as the one defined above. Similarly, the loweralkyl and the carboxy protecting group in the definition of R¹⁸ haveeach the same meaning as the one defined above.

Furthermore, piperidine derivatives represented by the formula (XVII) or(XVIII), their salts or hydrates thereof are also novel compounds. anduseful as the intermediates in the synthesis of the compounds of thepresent invention:

wherein R¹³, X⁵, l⁵ and Q¹ are each as defined above, provided that thefollowing cases are excluded: that in which, in the formula (XVII), X⁵is unsubstituted C₁₋₄ alkylene, l⁵ is 0 or 1 and Q¹ is ethoxycarbonyl,or X⁵ is unsubstituted C₁₋₃ alkylene, l⁵ is 0 or 1 and Q¹ is aminoprotected by carbonyl; and that in which, in the formula (XVIII), l¹ is0 and Q¹ is amino optionally protected by tert-butoxycarbonyl or hydroxyoptionally protected by methanesulfonyl; in particular, piperidinederivatives represented by the formula (XIX), (XX) or (XXI), their saltsor hydrates thereof are useful therefor:

wherein R¹³, X⁵, l⁵ and R¹⁸ are each as defined above;

and, in particular, piperidine derivatives selected from among thecompounds represented by the formulae 1), 2) or 3):

wherein R¹³ and R¹⁸ are each as defined above.

Now, general processes for synthesizing the compounds of the presentinvention will be illustrated.

wherein Ra and Ra′ represent each a carboxy protecting group; Hal.represents halogeno; Za represents a substituent of the ring G which isa pyrazine ring herein; and R′ represents:

1) lower alkyl;

2) optionally substituted arylalkyl;

3) optionally substituted heteroarylalkyl;

4) an amino protecting group;

5) a group represented by the formula:

 wherein X³, R⁹ and R¹⁰ are each as defined above; or

6) a group represented by the formula:

—X⁴—CO₂R¹¹

wherein X⁴ and R¹¹ are each as defined above.

[Step I]

A compound represented by the formula (1) is treated with a sulfurizingagent in a solvent such as ethanol in the presence of an alkali such assodium hydroxide to thereby give a compound of the formula (2). As thesulfurizing agent, use can be made of disodium disulfide, dilithiumdisulfide, etc. The reaction temperature preferably ranges from 25 to120° C., though it is not restricted thereto.

[Step II]

Next, the intermediate represented by the formula (2) is treated with ametal such as tin in a solvent such as ethanol in the presence of anacid such as hydrochloric acid to thereby give a compound of the formula(3).

[Step III]

Subsequently, the compound of the formula (3) is reacted with anappropriate alcohol or orthoester in the presence of an acid such ashydrochloric acid or sulfuric acid to thereby give a compoundrepresented by the formula (4).

[Step IV]

In a solvent such as dry N,N-dimethylformamide, the compound of theformula (4) is reacted with a dihalogenated pyrazine such as2,3-dichloropyrazine [formula (5)] to thereby give a compoundrepresented by the formula (6).

[Step VI]

The compound represented by the formula (6) or (9) is treated with areducing agent such as diisobutylaluminum hydride or aluminum lithiumhydride in a solvent to thereby give a compound represented by theformula (7) or (10). As the solvent, use can be made of dry ethers suchas dry tetrahydrofuran. The reaction is preferably effected at atemperature of −50 to 50° C.

[Step VI]

The compound represented by the formula (7) or (10) is treated with ahalogenating agent such as methanesulfonyl chloride in a solvent such asdry N,N-dimethylformamide in the presence of an appropriate base such aspyridine to thereby give a compound represented by the formula (8) or(11).

[Step VII]

The compound represented by the formula (6) is treated with a base suchas sodium hydride and a protecting group reagent such as methoxymethylchloride in a solvent to thereby give a compound represented by theformula (9).

[Step VIII]

The compound represented by, the formula (11) is treated with an acidsuch as hydrochloric acid or trifluoroacetic acid in a solvent tothereby give a compound represented by the formula (8).

wherein the rings A² and B, Y, m, the ring G, R′, Z, E, X, l and Hal.are each as defined above; and R^(13a) represents a lower alkyl or anamino protective group.

[Step IX]

A compound represented by the formula (12) is reacted with an acidchloride such as 1-chloroethyl chloroformate or vinyl chloroformateoptionally in a solvent. Next, an appropriate alcoholic solvent is addedthereto and reacted therewith. Alternatively, it is treated with anappropriate solvent containing hydrochloric acid or hydrobromic acid andthen heated in an alcoholic solvent. Alternatively, it is subjected to areduction reaction in a solvent such asmethanol/ethanol/tetrahydrofuran/ethyl acetate by using a metal catalystunder normal hydrogen pressure to elevated pressure. Thus, a compoundrepresented by the formula (13) can be obtained.

[Step X]

The compound represented by the formula (13) is treated with thecompound represented by the formula (8) or (11) obtained by theproduction process 1 in a solvent in the presence of an appropriate basesuch as anhydrous potassium carbonate or diisopropylamine to leave as itis give a compound represented by the formula (14). As the solvent, itis preferable to use a dry solvent such as dry N,N-dimethylformamide.The reaction is effected preferably at a temperature of 25 to 150° C. Ifnecessary, the compound represented by the formula (14) may be subjectedto optical resolution with the use of a chiral column, etc. to therebyseparate enantiomers from each other.

[Step XI]

When the compound represented by the formula (14) has an ester group asa substituent, this compound is hydrolyzed by reacting with anappropriate base in an aqueous solvent to thereby give a compound of theformula (16) having a carboxyl group.

In the above reaction, it is also possible to synthesize the compound ofthe formula (14) by using a protecting group of the functional groupcommonly employed in organic synthesis, then purifying the product by anappropriate operation commonly employed in the art such as silica gelcolumn chromatography and then deblocking the same.

[Step XXIV]

When the compound represented by the formula (14) has a carboxyl groupor an ester group as a substituent, the ester of the formula (14) may betreated with a reducing agent such as aluminum lithium hydride in a drysolvent such as tetrahydrofuran, diethyl ether or dimethoxyethane at 0°C. to room temperature to thereby give a compound having a terminalalcohol group represented by the formula (15).

wherein R^(13a) and the rings A² and B are each as defined above; R^(c)represents lower alkyl or a carboxy protecting group; R^(d) and R^(e)may be the same or different and each represents lower alkyl; and Trepresents optionally substituted lower alkylene, optionally substitutedlower alkenylene, optionally substituted lower alkynylene or optionallysubstituted arylene.

In the definition of T, the optionally substituted lower alkylene,optionally substituted lower alkenylene and optionally substituted loweralkynylene have each the same meaning as the one as will be definedbelow. On the other hand, the optionally substituted arylene means adivalent aromatic ring group optionally having substituent(s).Particular examples thereof include o-phenylene, m-phenylene,p-phenylene, methylphenylene and naphthylene groups.

[Step XII]

A compound of the formula (17), which is a commercially availableproduct or one obtained in accordance with, for example, the methoddescribed in Bull. Soc. Chim. Fr., 2981 (1989)., is subjected to theMannich reaction described in J.A.C.S., 84, 3139 (1962); Chem. Pharm.Bull., 11 (3), 333 (1963), etc. with an appropriate amine and anappropriate aldehyde in a solvent to thereby give a compound representedby the formula (18). As the solvent, use can be made of ethanol,methanol, acetic acid, etc. The reaction is effected preferably at from25° C. to the reflux temperature.

[Step XIII]

The compound represented by the formula (18) is reacted with anappropriate Wittig-Horner-Emmons reagent in a solvent in the presence ofan appropriate base to thereby give a compound represented by theformula (19). As the solvent, use can be made of dry solvents such asN,N-dimethylformamide, tetrahydrofuran or diethyl ether. As the base,use can be made of sodium hydride, potassium tert-butoxide,n-butyllithium, etc. The reaction can be effected at from −100° C. tothe boiling point of the solvent.

[Step XIV]

The compound represented by the formula (19) is reduced with the use ofan appropriate metal or an appropriate metal catalyst in a solvent tothereby give a compound represented by the formula (20). The compound ofthe formula (20) can be obtained by, for example, using a catalyst suchas palladium in a solvent such as methanol, ethanol or ethyl acetateunder normal to elevated hydrogen pressure, or treating the compound(19) with magnesium in a solvent such as methanol.

[Step XV]

Compounds represented by the formula (20), (24), etc. are reacted with abase such as lithium diisopropylamide in a dry solvent such as diethylether or tetrahydrofuran and then reacted with an alkyl halide tothereby give compounds represented by the formula (21), (25), etc.respectively. The reaction temperature preferably ranges from −100 to25° C.

[Step XVI]

The compound represented by the formula (18) is treated with acyanidation reagent such as tosylmethyl isocyanide (TosMic) in a mixtureof a solvent such as dimethoxyethane, tetrahydrofuran or diethyl etherwith an alcoholic solvent such as tert-butanol in the presence of a basesuch as potassium tert-butoxide to thereby give a cyano compoundrepresented by the formula (22). It is preferable to effect thisreaction at a temperature of 0 to 100° C.

[Step XVII]

The cyano compound of the formula (22), etc. is treated with a base suchas sodium hydroxide or potassium hydroxide in an alcoholic solvent suchas ethanol, propanol, ethylene glycol or diethylene glycol and heatedunder reflux to thereby give a carboxylic acid represented by theformula (23), etc.

[Step XVIII]

The compound of the formula (23), etc. is treated with an activator suchas thionyl chloride in an alcoholic solvent such as methanol or ethanolto thereby give an ester of the formula (24), etc. The reactiontemperature preferably ranges from 0° C. to room temperature.

[Step XIX]

A dihalomethane such as dibromomethane or diuodomethane is treatedsuccessively with a lithium amide such as lithium2,2,6,6-tetramethylpiperidine and the ester of the formula (24), etc.After further treating with a base, the obtained product is hydrolyzedto thereby give an ester represented by the formula (26), etc. As asolvent, it is preferable to use tetrahydrofuran, diethyl ether, etc.The reaction temperature ranges from −90° C. to room temperature.

[Step XXI]

An alcohol represented by the formula (33) is treated with a base suchas sodium hydride or sodium methoxide and then reacted with ahalogenated acetate such as an alkyl iodoacetate such as ethyliodoacetate to thereby give an ether represented by the formula (34).When a phenol derivative is employed as an alkylating agent, an etherrepresented by the formula (34) can be obtained by the so-calledMitsunobu reaction with the use of a condensing agent such as diethylazadicarboxylate and triphenylphosphine.

wherein the rings A² and B, R^(13a), R^(c), R^(d) and R^(e) are each asdefined above.

[Step XX]

An ester such as methyl acetate or ethyl acetate is treated with a basesuch as lithium diisopropylamide and reacted with a ketone representedby the formula (18). Thus a β-hydroxyacetate represented by the formula(27) can be obtained. As the solvent, it is appropriate to use diethylether, tetrahydrofuran, etc. The reaction temperature ranges from −78°C. to room temperature.

[Step XXI]

The alcohol represented by the formula (27) is treated with a base suchas sodium hydride or sodium methoxide and then reacted with an alkylhalide such as methyl iodide or ethyl iodide in a solvent such asdimethoxyethane, tetrahydrofuran or N,N-dimethylformamide to therebygive an ether represented by the formula (28). When a phenol derivativeis employed as an alkylating agent, an ether represented by the formula(28) can be obtained by the so-called Mitsunobu reaction with the use ofa condensing agent such as diethyl azadicarboxylate andtriphenylphosphine.

[Step XXII]

(Methoxymethyl)trimethylsilane, methoxymethyl dimethylphosphonate, etc.is treated with a strong base such as butyllithium in a dry solvent suchas tetrahydrofuran, dimethoxyethane or diethyl ether to thereby give anenol ether. Next, this product is hydrolyzed with an acid such ashydrochloric acid, sulfuric acid or acetic acid in an alcoholic solventsuch as methanol or ethanol to thereby give an aldehyde having one morecarbon atom as represented by the formula (29), etc.

[Step XXIII]

A dithiane such as 2-trimethyl-1,3-dithiane is reacted with a strongbase such as butyllithium and the anion thus obtained is reacted withthe aldehyde represented by the formula (29). The crude dithiane thusobtained is then treated with a metal salt such as mercury chloride tothereby give an ester represented by the formula (32).

[Step XIII]

The compound represented by the formula (29) is reacted with anappropriate Wittig-Horner-Emmons reagent in a solvent in the presence ofan appropriate base to thereby give a compound represented by theformula (30). As the solvent, use can be made of dry solvents such asN,N-dimethylformamide, tetrahydrofuran or diethyl ether. As the base,use can be made of sodium hydride, potassium tert-butoxide,n-butyllithium, etc. The reaction can be effected at from −10° C. to theboiling point of the solvent.

[Step XIV]

The compound represented by the formula (30) is reduced with the use ofan appropriate metal or an appropriate metal catalyst in a solvent tothereby give a compound represented by the formula (31). The compound ofthe formula (31) can be obtained by, for example, using a catalyst suchas palladium in a solvent such as methanol, ethanol or ethyl acetateunder normal to elevated hydrogen pressure, or treating the compound(30) with magnesium in a solvent such as methanol.

wherein the rings A² and B, R^(13a), R^(c) and R^(d) are each as definedabove; R^(13b) represents lower alkyl or an amino protective group; andAc represents acetyl.

[Step XXV]

An amine represented by the formula (20) is treated with an aminoprotecting group such as vinyl chloroformate optionally in anappropriate solvent such as 1,2-dichloroethane at 0° C. to the refluxtemperature to thereby give an amine protected with vinylformaterepresented by the formula (38). It is preferable that R^(13b) is acarbamate-type amino protecting group, still more preferablyvinyloxycarbonyl.

[Step XI]

A compound represented by the formula (38) is reacted with anappropriate base in an aqueous solvent and then hydrolyzed to therebygive a compound of the formula (39) having a carboxyl group.

[Step XXVI]

The carboxylic acid represented by the formula (39) is reacted withactive esterifying agents such as N-hydroxysuccinimide withN,N-dicyclohexylcarbodiimide or a base such as triethylamine with ethylchloroformate to thereby give an active acid anhydride. This is thentreated with an appropriate reducing agent such as sodium borohydride tothereby give an alcohol represented by the formula (37).

[Step XXIV]

Similarly to the above-mentioned procedure, the ester represented by theformula (20) is treated with a reducing agent such as aluminum lithiumhydride in a dry solvent such as tetrahydrofuran, diethyl ether ordimethoxyethane to thereby give an alcohol represented by the formula(33).

[Step XXVII]

The alcohol represented by the formula (33) is treated with aceticanhydride or acetyl chloride in an appropriate solvent in the presenceof pyridine as a base to thereby give an ester represented by theformula (35).

[Step XXV]

Similarly to the above-mentioned procedure, the amine compoundrepresented by the formula (35) is treated with an amino protectinggroup such as vinyl chloroformate optionally in an appropriate solventsuch as 1,2-dichloroethane at 0° C. to the reflux temperature to therebygive an amine protected by vinylformate represented by the formula (36).R^(13b) is preferably a carbamate-type protecting group, though it isnot restricted to such.

[Step XI]

Similarly to the above-mentioned procedure, the compound represented bythe formula (36) is reacted with an appropriate base in an aqueoussolvent and then hydrolyzed to thereby give a compound of the formula(37) having a hydroxyl group.

[Step XXVIII]

The alcohol represented by the formula (37) is reacted with anactivating reagent such as methanesulfonyl chloride or p-toluenesulfonylchloride in the presence of an appropriate base such as pyridine. Next,it is treated with a cyaniding agent such as sodium cyanide or potassiumcyanide in an aprotic polar solvent such as dimethyl sulfoxide tothereby give a cyano compound represented by the formula (40). Thisreaction can be effected from room temperature to the boiling point ofthe solvent.

[Step XVII]

Similarly to the above-mentioned procedure, the cyano compound of theformula (40) is treated with a base such as sodium hydroxide orpotassium hydroxide in an alcoholic solvent such as ethanol, propanol,ethylene glycol or diethylene glycol and heated under reflux to therebygive a carboxylic acid of the formula (41).

[Step XVIII]

Similarly to the above-mentioned procedure, the compound of the formula(41) is treated with an activator such as thionyl chloride in analcoholic solvent such as methanol or ethanol to thereby give an esterof the formula (42). The reaction temperature preferably ranges from 0°C. to room temperature.

[Step XXIX]

A solution of the alcohol represented by the formula (37) in, forexample, methylene chloride is added to a reaction mixture obtained fromoxalyl chloride and dimethyl sulfoxide and treated with a base such astriethylamine, i.e., the so-called Swern oxidation. Thus, an aldehyderepresented by the formula (43) can be obtained.

[Step XIII]

The compound represented by the formula (43) is reacted with anappropriate Wittig-Horner-Emmons reagent in a solvent in the presence ofan appropriate base to thereby give a compound represented by theformula (44). As the solvent, use can be made of dry solvents such asN,N-dimethylformamide, tetrahydrofuran or diethyl ether. As the base,use can be made of sodium hydride, potassium tert-butoxide, n-butyllithium, etc. The reaction can be effected at from 31 10° C. to theboiling point of the solvent.

[Step IX]

The compound represented by the formula (44) is treated with anappropriate solvent containing hydrobromic acid and then heated in analcoholic solvent to thereby give a compound represented by the formula(45).

[Step XIV]

Similarly to the above-mentioned procedure, the compound represented bythe formula (45) is reduced by the use of an appropriate metal or anappropriate metal catalyst in a solvent to thereby give a compoundrepresented by the formula (46). The compound of the formula (46) can beobtained by, for example, using a catalyst such as palladium in asolvent such as methanol, ethanol or ethyl acetate under normal toelevated hydrogen pressure, or treating the compound (45) with magnesiumin a solvent such as methanol.

wherein the rings A² and B, R^(13a), R^(c), R^(d) and l are each asdefined above; and M represents an optionally substituted lower alkyleneoptionally having a heteroatom, optionally substituted lower alkenyleneoptionally having a heteroatom, optionally substituted lower alkynyleneoptionally having a heteroatom or optionally substituted aryleneoptionally having a heteroatom.

In the definition of M, the optionally substituted lower alkyleneoptionally having a heteroatom, the optionally substituted loweralkenylene optionally having a heteroatom and the optionally substitutedlower alkynylene optionally having a heteroatom have each the samemeaning as the one defined above, while the optionally substitutedarylene optionally having a heteroatom means an optionally substituteddivalent aromatic ring group optionally having a heteroatom. Particularexamples of the divalent aromatic ring group include o-phenylene,m-phenylene, p-phenylene, methylphenylene and naphthylene groups.

[Step XXX]

A ketone represented by the formula (47) is reacted with a thioalcoholsuch as ethanedithiol in the presence of a boron trifluoride complex ina solvent such as dichloromethane to thereby give a thioketalrepresented by the formula (48).

[Step XXXI]

The thioketal represented by the formula (48) is treated with a reducingreagent such as Raney nickel to thereby give a compound represented bythe formula (49). As a solvent, use can be made of ethanol, methanoletc. The reaction is preferably effected at the reflux temperature ofthe solvent.

[Step XIX]

Similarly to the above-mentioned procedure, a dihalomethane such asdibromomethane or diiodomethane is treated successively with a lithiumamide such as lithium 2,2,6,6-tetramethylpiperidine and the ester of theformula (49). After further treating with base, the obtained product ishydrolyzed with an acid to thereby give an ester represented by theformula (50). As a solvent, it is preferable to use tetrahydrofuran,diethyl ether, etc. The reaction temperature ranges from −90° C. to roomtemperature.

wherein the rings A² and B, R^(13a), R^(13b), R^(c) and n are each asdefined above.

[Step XXXII]

Methyltriphenylphosphonium bromide is treated with an appropriate basesuch as potassium tert-butoxide or butyllithium in a solvent such astoluene, xylene or tetrahydrofuran. Next, ketones represented by theformulae (18) and (54) are reacted therewith to thereby give compoundsrepresented by the formulae (51) and (55). The reaction temperaturepreferably ranges from −78° C. to room temperature.

[Step IX]

Similarly to the above-mentioned procedure, the compound represented bythe formula (51) is reacted with an acid chloride such as 1-chloroethylchloroformate or vinyl chloroformate optionally in a solvent. Next, anappropriate alcoholic solvent is added thereto and reacted therewith.Alternatively, it is treated with an appropriate solvent containinghydrochloric acid or hydrobromic acid and then heated in an alcoholicsolvent. Alternatively, it is subjected to a reduction reaction in asolvent such as methanol/ethanol/tetrahydrofuran/ethyl acetate by usinga metal catalyst under normal to elevated hydrogen pressure. Thus, acompound represented by the formula (52) can be obtained.

[Step XXXIII]

The compound represented by the formula (52) is reacted with, forexample, di-tert-butyl dicarbonate as an amino protecting grouppreferably at 0° C. to room temperature in the presence of a base suchas pyridine, diisopropylethylamine or triethylamine in an appropriatesolvent such as methanol to thereby give a compound represented by theformula (53). R^(13b) may be arbitrary, so long as it is a lower alkylor an amino protecting group. Preferable examples of the aminoprotecting group as R^(13b) are those which can be converted intocarbamate, amide, sulfonamide, etc. after the introduction of theprotecting group. For example, butoxycarbonyl is preferable therefor.

[Step XXXIV]

The compound represented by the formula (53) is treated with zinc/copperalloy and trichloroacetyl chloride in a dry solvent such as diethylether, dimethoxyethane or tetrahydrofuran to thereby give a crudedichlorobutanone compound. Then the crude product thus obtained istreated with a reducing agent such as ammonium chloride/zinc in methanolto thereby give a spiroketone compound represented by the formula (54).The reaction temperature preferably ranges from 0 to 50° C.

[Step XXXV]

An exo-methylene compound represented by the formula (55) is treatedwith an appropriate borane compound such as a borane/tetrahydrofurancomplex in an appropriate solvent such as dry tetrahydrofuran ordimethoxyethane followed by treatment with an oxidizing agent such ashydrogen peroxide in an alkaline solution. Thus, an alcohol compoundrepresented by the formula (56) can be obtained.

[Step XXIX]

Similarly to the above-mentioned procedure, a solution of the alcoholrepresented by the formula (56) in, for example, methylene chloride isadded to a reaction mixture obtained from oxalyl chloride and dimethylsulfoxide and treated with a base such as triethylamine, i.e., theso-called Swern oxidation. Thus, an aldehyde represented by the formula(57) can be obtained.

[Step XXXVI]

The compound represented by the formula (57) is treated with brominepreferably at 0° C. to room temperature in an appropriate alcoholicsolvent such as methanol or ethanol in the presence of an alkaline basesuch as sodium hydrogencarbonate or potassium carbonate to thereby givean ester compound represented by the formula (58).

[Step XIII]

Similarly to the above-mentioned procedure, the compound represented bythe formula (54) is reacted with an appropriate Wittig-Horner-Emmonsreagent in a solvent in the presence of an appropriate base to therebygive a compound represented by the formula (59). As the solvent, use canbe made of dry solvents such as N,N-dimethylformamide, tetrahydrofuranor diethyl ether. As the base, use can be made of sodium hydride,potassium tert-butoxide, n-butyllithium, etc. The reaction can beeffected at −100° C. to the boiling point of the solvent.

[Step XIV]

Similarly to the above-mentioned procedure, the compound represented bythe formula (59) is reduced by the use of an appropriate metal or anappropriate metal catalyst in a solvent to thereby give a compoundrepresented by the formula (60). The compound of the formula (60) can beobtained by, for example, using a catalyst such as palladium in asolvent such as methanol, ethanol or ethyl acetate under normal toelevated hydrogen pressure, or treating the compound (59) with magnesiumin a solvent such as methanol.

wherein the rings A² and B and R^(13a) are each as defined above.

[Step XXI]

A compound represented by the formula (61) is treated with a base suchas sodium hydride or sodium methoxide and then reacted with a compoundof the formula (62) in a solvent such as dimethoxyethane,tetrahydrofuran or N,N-dimethylformamide to thereby give a compoundrepresented by the formula (63).

[Step XXXVII]

The compound represented by the formula (63) is treated in1,2-dichloroethane employed as a solvent successively withtrifluoromethanesulfonic anhydride and a base such as collidine tothereby give a cyclized product represented by the formula (64).

wherein the rings A² and B, R^(13a), R^(c), Y and m are each as definedabove.

[Step XXXVIII]

A coumarate derivative represented by the formula (65) is reacted with acompound represented by the formula (66) under heating preferably at 80to 150° C. to thereby give cyclized products represented by the formulae(67) and (67′).

[Step XXXIX]

A compound represented by the formula (67) is cyclized by heating,optionally in an appropriate solvent, to thereby give a tricycliccompound represented by the formula (68). The compound of the formula(69) can be synthesized from the compound (67′) also under the sameconditions too. The reaction is preferably effected at 100 to 200° C.

[Step XXXX]

The amide compounds represented by the formulae (68), (71) and (72) aretreated with a thioamidation agent such as a Lawson reagent in a solventsuch as benzene, toluene or xylene to thereby give crude thioamidecompounds. These crude products are treated with an alkylating agentsuch as methyl iodide in a solvent such as tetrahydrofuran,dimethoxyethane or diethyl ether preferably at room temperature tothereby give reduced compounds represented by the formulae (70), (73)and (74) respectively.

[Step XIV]

Similar to the above-mentioned procedure, the compounds represented bythe formulae (68) and (69) are reduced by the use of an appropriatemetal or an appropriate metal catalyst in a solvent to thereby givecompounds represented by the formulae (71) and (72). These products canbe obtained by, for example, using a catalyst such as palladium in asolvent such as methanol, ethanol or ethyl acetate under normal toelevated hydrogen pressure, or treating the starting compounds withmagnesium in a solvent such as methanol.

wherein the rings A², B and G, R, R^(13a), R^(13b), R^(c), R^(e), Z, E,X and l are each as defined above.

[Step XXXXI]

A compound represented by the formula (20) is treated with analkyllithium such as methyllithium or ethyllithium or a Grignard reagentsuch as a methylmagnesium halide in a solvent such as drytetrahydrofuran, diethyl ether or dimethoxyethane at −78° C. to theboiling point of the solvent to thereby give an alcohol represented bythe formula (75).

[Step IX]

Similarly to the above-mentioned procedure, a compound represented bythe formula (37) is reacted with an acid chloride such as 1-chloroethylchloroformate or vinyl chloroformate optionally in a solvent. Next, anappropriate solvent is added thereto and reacted therewith.Alternatively, it is treated with an appropriate solvent containinghydrochloric acid or hydrobromic acid and then heated in an alcoholicsolvent. Thus, a compound represented by the formula (78) can beobtained.

[Step XXVI]

Similarly to the above-mentioned procedure, an acid represented by theformula (16) is reacted with a reducing agent such as aluminum lithiumhydride in a dry solvent such as tetrahydrofuran, diethyl ether ordimethoxyethane to thereby give an alcohol represented by the formula(84).

wherein the rings A² and B, R^(13a) and R^(c) are each as defined above;and R^(e′) represents lower alkyl.

[Step IX]

Similarly to the above-mentioned procedure, a compound represented bythe formula (20) or (21) is reacted with an acid chloride such as1-chloroethyl chloroformate or vinyl chloroformate optionally in asolvent. Next, an appropriate alcoholic solvent is added thereto andreacted therewith. Alternatively, it is treated with an appropriatesolvent containing hydrochloric acid or hydrobromic acid and then heatedin an alcoholic solvent. Thus, a compound represented by the formula(76) can be obtained.

[Step XXIV]

Similarly to the above-mentioned procedure, an ester represented by theformula (76) is treated with a reducing agent such as aluminum lithiumhydride in a dry solvent such as tetrahydrofuran, diethyl ether ordimethoxyethane at 0° C. to room temperature to thereby give an alcoholrepresented by the formula (77).

wherein the rings A² and B, R^(13a) and R^(13b) are each as definedabove; and R^(p) represents a hydroxy protective group.

The term “hydroxy protective group” as used in the definition of R^(p)has the same meaning as the one defined above.

[Step XXIV]

Similarly to the above-mentioned procedure, an aldehyde represented bythe formula (29) is treated with a reducing agent such as aluminumlithium hydride in a dry solvent such as tetrahydrofuran, diethyl etheror dimethoxyethane at 0° C. to room temperature to thereby give analcohol represented by the formula (79).

[Step XXVII]

Similarly to the above-mentioned procedure, the alcohol represented bythe formula (79) is treated with, for example, acetic anhydride oracetyl chloride as a hydroxy protective group in an appropriate solventin the presence of pyridine as a base to thereby give an esterrepresented by the formula (80).

[Step XXV]

Similarly to the above-mentioned procedure, the amine represented by theformula (80) is treated with an amino protecting group such as vinylchloroformate optionally in an appropriate solvent such as1,2-dichloroethane at 0° C. to the reflux temperature to thereby give anamine protected by vinylformate represented by the formula (81). R^(13b)is preferably a carbamate type amino protecting group, in particular,vinyloxycarbonyl.

[Step XI]

Similarly to the above-mentioned procedure, the compound represented bythe formula (81) is reacted with an appropriate base in an aqueoussolvent and then hydrolyzed to thereby give a compound of the formula(82) having a hydroxyl group.

[Step IX]

The compound represented by the formula (82) is reacted with anappropriate solvent containing hydrochloric acid or hydrobromic acid andthen heated in an alcoholic solvent to thereby give a compoundrepresented by the formula (83).

Production Process 8

The compounds of the present invention can be synthesized by using theabove-mentioned methods or combining publicly known organic synthesismethods. Now, particular methods for synthesizing preferable compoundswill be illustrated.

wherein R^(13a) and R^(c) and Hal. are each as defined above; R^(f),R^(z) and R^(h) represent substitutents, having the same meaning as thatdefined above, of the rings A and B which are respectively a piperidinering and a cyclohexyl ring having Qa; and Za represents a substituent,containing the same meaning as the one defined above, of the ring Gwhich is a pyrazine ring.

This compound can be synthesized by combining the above-mentionedprocedures.

[Step XII]

A compound of the formula (17a), which is a commercially availableproduct or one obtained in accordance with, for example, the methoddescribed in Bull. Soc. Chim. Fr., 2981 (1989), is subjected to theMannich reaction described in J.A.C.S., 84, 3139 (1962) and Chem. Pharm.Bull., 11 (3), 333 (1963) with an appropriate amine and an appropriatealdehyde in a solvent to thereby give a compound represented by theformula (18a). As the solvent, use can be made of ethanol, methanol,acetic acid, etc. The reaction is preferably effected at 25° C. to thereflux temperature.

[Step XIII]

The compound represented by the formula (18a) is reacted with anappropriate Wittig-Horner-Emmons reagent in a solvent in the presence ofan appropriate base to thereby give a compound represented by theformula (19a). As the solvent, use can be made of dry solvents such asN,N-dimethylformamide, tetrahydrofuran or diethyl ether. As the base,use can be made of sodium hydride, potassium tert-butoxide,n-butyllithium, etc. The reaction can be effected at −100° C. to theboiling point of the solvent.

[Step XIV]

The compound represented by the formula (19a) is reduced by the use ofan appropriate metal or an appropriate metal catalyst in a solvent tothereby give a compound represented by the formula (20a). The compoundof the formula (20a) can be obtained by, for example, using a catalystsuch as palladium in a solvent such as methanol, ethanol or ethylacetate under normal to elevated hydrogen pressure, or treating thecompound (19a) with magnesium in a solvent such as methanol.

[Step XV]

The compound represented by the formula (20a) is reacted with a basesuch as lithium diisopropylamide in a dry solvent such as diethyl etheror tetrahydrofuran and then reacted with an alkyl halide to thereby givea compound represented by the formula (21a). The reaction temperaturepreferably ranges from −100 to 25° C.

[Step IX]

The compounds represented by the formulae (20a) and (21a) are treatedwith an acid chloride such as 1-chloroethyl chloroformate or vinylchloroformate optionally in a solvent. Next, an appropriate solvent suchas an alcohol is added thereto and reacted therewith. Alternatively, itis treated with an appropriate solvent containing hydrochloric acid orhydrobromic acid and then heated in an alcoholic solvent. Thus, acompound represented by the formula (85) can be obtained.

[Step X]

The compound represented by the formula (85) is treated with thecompound represented by the formula (8) obtained by the productionprocess 1 in a solvent in the presence of an appropriate base such asanhydrous potassium carbonate or diisopropylamine to thereby give acompound represented by the formula (86). As the solvent, it ispreferable to use a dry solvent such as dry N,N-dimethylformamide. Thereaction is preferably effected at a temperature of 25 to 150° C. Ifnecessary, the compound represented by the formula (86) may be subjectedto optical resolution with the use of a chiral column, etc. to therebyseparate enantiomers from each other.

[Step XI]

The compound represented by the formula (86) is reacted with anappropriate base in an aqueous solvent and then hydrolyzed to therebygive a compound of the formula (87).

In the above reaction, it is also possible to synthesize the product byusing a protecting group of the functional group commonly employed inorganic synthesis, then purifying the product by an appropriateoperation commonly employed in the art such as silica gel columnchromatography and then deblocking the same.

wherein G, Z, E, X², I² Q and Hal are each as defined above; and B¹represents hydroxymethyl, halide, methoxy, methoxymethyl, lower alkyl oralkoxycarbonyl.

[Step XXXXII]

The compounds represented by the formulae (90) and (92) are treated witha base such as sodium hydride and then reacted with a halogen compoundof the formula (89) in a solvent such as dry N,N-dimethylformamide ortetrahydrofuran to thereby give the compounds of the formulae (91) and(93) respectively. Similarly, a compound represented by the formula (96)can be obtained from the compounds (92) and (95).

[Step IV]

The compound of the formula (92) is reacted with a dihalogenatedheteroaryl compound as the one represented by the formula (89) in asolvent such as dry N,N-dimethylformamide to thereby give a compoundrepresented by the formula (94).

[Step XXXXIII]

The compound represented by the formula (91) is treated with a reducingagent such as iron in a solvent mixture of an alcohol, tetrahydrofuranand water in the presence of ammonium chloride. Alternatively, it istreated with hydrosulfite sodium in a solvent mixture of tetrahydrofuranwith water. Thus, an amine represented by the formula (93) can beproduced. As the alcohol, use can be made of methanol, ethanol andisopropanol. In some cases, the intermediate (93) undergoes ring closureand thus a tricycloheteroaryl derivative represented by the formula (94)can be directly obtained.

[Step XXXXIV]

The amine represented by the formula (93) is heated in an appropriatesolvent to thereby give a tricycloheteroaryl derivative represented bythe formula (94). As the solvent, use can be made of alcohols such asmethanol or ethanol, dry N,N-dimethylformamide, etc. It is also possibleto use an acid such as hydrochloric acid, acetic acid orp-toluenesulfonic acid as a catalyst. The reaction is effectedpreferably at 50° C. to the reflux temperature.

[Step XXXXV]

The compound represented by the formula (96) is heated in an appropriatesolvent in the presence of an oxidizing agent and an acid.Alternatively, it is reacted with a base in an appropriate solvent inthe presence of an oxidizing agent. Thus a tricycloheteroaryl derivativerepresented by the formula (94) can be obtained. As the oxidizing agent,use can be made of iodine, sulfur, etc. As the acid, use can be made ofacetic acid, etc. As the base, use can be made of sodium hydride. As thesolvent, use can be made of diphenyl ether, dry N,N-dimethylformamide,etc. The reaction can be carried out at 0 to 200° C.

wherein G, Z, E, X², I², Q and B¹ are each as defined above; and α is 0or 1.

[Step XXXXII]

The compound represented by the formula (92) is treated with a base suchas sodium hydride and then reacted with a halogen compound (97) in asolvent such as dry N,N-dimethylformamide or tetrahydrofuran to therebygive a compound represented by the formula (98).

[Step XXXXVI]

When α is 1, the amine represented by the formula (98) is reacted with acarboxylic anhydride, phosphoric anhydride and an acid halide optionallyin an appropriate solvent in the presence of an appropriate base such aspyridine, triethylamine or N,N-diisopropylethylamine to thereby give anamide represented by the formula (99). As the solvent, use can be madeof dry dichloromethane, etc. The reaction can be carried out at 0° C. tothe reflux temperature.

[Step XXXXV]

The compound represented by the formula (99) is heated in an appropriatesolvent in the presence of an oxidizing agent and an acid.Alternatively, it is reacted with a base in an appropriate solvent inthe presence of an oxidizing agent. Thus a tricycloheteroaryl derivativerepresented by the formula (100) can be obtained. As the oxidizingagent, use can be made of iodine, sulfur, etc. As the acid, use can bemade of acetic acid, etc. As the base, use can be made of sodiumhydride. As the solvent, use can be made of diphenyl ether, dryN,N-dimethylformamide, etc. The reaction can be carried out at 0 to 200°C.

wherein G, Z, E, X², I², Q, R, R′ and R^(a) are each as defined above.

[Step VII]

An amine represented by the formula (101) is treated with a base such assodium hydride and a protective reagent such as methoxymethyl chloridein a solvent to thereby give a compound represented by the formula(105).

[Step V]

The compound represented by the formula (101) or (105) is treated with areducing agent such as diisobutylaluminum hydride or aluminum lithiumhydride in a solvent to thereby give a compound represented by theformula (102) or (106). As the solvent, use can be made of drytetrahydrofuran, dry diethyl ether, etc. The reaction is preferablyeffected at a temperature of −50° C. to the reflux temperature.

[Step VI]

The compound represented by the formula (102) or (106) is treated with ahalogenating agent such as methanesulfonyl chloride in a solvent such asdry N,N-dimethylformamide in the presence of an appropriate base such aspyridine, triethylamine or N,N-diisopropylethylamine to thereby give acompound represented by the formula (103) or (107).

[Step XXIX]

Similar to the above-mentioned procedure, a solution of the compoundrepresented by the formula (102) or (106) in, for example, methylenechloride is added to a reaction mixture obtained from oxalyl chlorideand dimethyl sulfoxide and treated with a base such as triethylamine.Alternatively, it is treated with pyridinium dichromate in a solventsuch as dichloromethane or N,N-dimethylformamide or treated withmanganese dioxide in a solvent such as dichloromethane. Thus, analdehyde represented by the formula (104) or (108) can be obtained.

wherein the rings A¹ and A³, G, Z, E, X¹, I¹, M, R, R′, R^(13a) and Halare each as defined above.

[Step IX]

A compound represented by the (110) or (117) is treated in the followingmanner. 1) When R^(13a) is alkyl, etc., the starting compound is reactedwith an acid chloride such as 1-chloroethyl chloroformate or vinylchloroformate optionally in a solvent. Next, an appropriate alcoholicsolvent is added thereto and reacted therewith. Alternatively, it istreated with an appropriate solvent containing hydrochloric acid orhydrobromic acid and then heated in an alcoholic solvent. 2) WhenR^(13a) is tert-butoxycarbonyl, etc., the starting compound is reactedwith an appropriate acid such as acetic acid, trifluoroacetic acid orhydrochloric acid optionally in an appropriate solvent such asdichloromethane or tetrahydrofuran. 3) When R^(13a) is a protectivegroup which can be eliminated, such as benzyl, the starting compound ishydrogenated in an appropriate solvent such as methanol, ethanol, ethylacetate or tetrahydrofuran by using a metal catalyst such as palladiumor platinum (IV) oxide under normal to elevated hydrogen pressure. Thus,a compound represented by the formula (111) or (118) can be obtained.

[Step X]

The compound represented by the formula (111) or (118) is treated with ahalide represented by the formula (112) in a solvent in the presence ofan appropriate base such as anhydrous potassium carbonate orN,N-diisopropylethylamine to thereby give a compound represented by theformula (113) or (119). As the solvent, use can be made ofN,N-dimethylformamide, etc. The reaction can be effected at atemperature of 0 to 150° C.

[Step VIII]

When R in the compounds represented by the formulae (113), (116), (119)and (122) is methoxymethyl, these compounds are treated with anappropriate acid such as acetic acid, trifluoroacetic acid orhydrochloric acid optionally in a solvent such as dichloromethane ortetrahydrofuran/water to thereby give compounds represented by theformulae (114), (115), (120) and (121). The reaction can be effected at0° C. to the reflux temperature of the solvent.

[Step XI]

When the compounds represented by the formulae (113), (114), (119) and(120) have an ester group in the molecule, these compounds are treatedwith an appropriate base in an aqueous solvent to thereby give compoundsrepresented by the formulae (116), (115), (122) and (121) respectively.As the solvent, use can be made of alcoholic solvents such as methanolor ethanol or solvent mixtures such as alcohol/tetrahydrofuran/water. Asthe base, use can be made of sodium hydroxide or potassium hydroxide.The reaction can be carried out at room temperature to the refluxtemperature of the solvent.

wherein the ring A³, M and R^(13a) are each as defined above; R^(j)represents hydrogen, fluorine or optionally substituted lower alkyl; EWGrepresents ester, nitrile, optionally substituted phenyl, etc.; A⁷represents: 1) the same group as A³; or 2) a bicyclic ring AB whereinthe bridgehead carbon atoms are directly bonded to each other; R^(s)represents optionally substituted C₀₋₆ alkylene; and R^(t) representshydrogen or lower alkyl, or, in some cases, neither R^(s) nor R^(t)exists and the carbon atom in the side chain to which R^(s) and R^(t)are bonded in the formula is one of the members of the ring A⁷.

[Step XIII]

The compound represented by the formula (124) is reacted with anappropriate Horner-Emmons reagent in a solvent in the presence of anappropriate base to thereby give a compound represented by the formula(125). As the solvent, use can be made of dry solvents such asN,N-dimethylformamide, tetrahydrofuran or diethyl ether. As the base,use can be made of sodium hydride, potassium tert-butoxide,n-butyllithium, lithium diisopropylamide, etc. The reaction can beeffected at −100° C. to the reflux temperature of the solvent.

[Step XIV]

The compound represented by the formula (125) is subjected to areduction reaction in a solvent with the use of an appropriate metalcatalyst to thereby give a compound represented by the formula (126).The reaction can be effected in a solvent such as methanol, ethanol,ethyl acetate or tetrahydrofuran with the use of palladium, platinum(IV) oxide, etc. under normal to elevated hydrogen pressure.

wherein M, R^(13a), A³, R⁵ and R^(t) are each as defined above.

[Step XXIV]

A compound represented by the formula (127) or (129) is treated with areducing agent such as aluminum lithium hydride in a solvent to therebygive a compound represented by the formula (128) or (130). As thesolvent, use can be made of dry solvents such as tetrahydrofuran,diethyl ether or dimethoxyethane.

The reaction can be effected at −50° C. to the reflux temperature.

wherein G, Z, E, X¹, l¹, R′ and Hal are each as defined above.

[Step X]

A compound represented by the formula (131) is treated with anappropriately protected 3-aminomethylpyridine derivative in a solvent inthe presence of an appropriate base such as anhydrous potassiumcarbonate or N,N-diisopropylamine to thereby give a compound representedby the formula (132). As the solvent, use can be made of ethanol, dryN,N-dimethylformamide, etc. The reaction can be effected at atemperature of 0 to 150° C.

[Step XXIV]

The compound represented by the formula (132) is treated with a reducingagent such as aluminum lithium hydride in a solvent to thereby give acompound represented by the formula (133). As the solvent, use can bemade of methanol, ethanol, etc. The reaction can be effected at 0° C. tothe reflux temperature.

[Step XXIV]

The compound represented by the formula (133) is treated with a reducingagent such as aluminum lithium hydride in a solvent to thereby give acompound represented by the formula (134). As the solvent, it ispreferable to use isopropyl alcohol. It is preferable to effect thereaction at 50° C. to the reflux temperature.

[Step VIII]

The compound represented by the formula (134) is treated with anappropriate acid such as acetic acid, trifluoroacetic acid orhydrochloric acid optionally in a solvent such as dichloromethane ortetrahydrofuran/water to thereby give a compound represented by theformula (135). Although the reaction can be effected at 0° C. to thereflux temperature of the solvent, it is carried out in acetic acid at80° C. in the most desirable case.

[Step XXXXVII]

The amine represented by the formula (135) is reacted withmethanesulfonic anhydride or the acid halide optionally in anappropriate solvent such as dichloromethane in the presence of anappropriate base such as pyridine, triethylamine or N,N-diisopropylamineto thereby give a compound represented by the formula (136).

wherein G, Z, E, X¹, l¹, M, R^(13a), R^(13b), A³ and Hal are each asdefined above.

[Step XXXIII]

A compound represented by the formula (137) is reacted with, forexample, di-tert-butyl dicarbonate as an amino protective grouppreferably at 0° C. to room temperature in the presence of a base suchas pyridine, triethylamine or N,N-diisopropylethylamine in anappropriate solvent such as methanol or dichloromethane to thereby givea compound represented by the formula (138). R^(13b) may be an arbitraryone, so long as it is lower alkyl or an amino protective group. The mostdesirable example of R^(13b) is an alkyl carbamate.

[Step IX]

The compound represented by the (138) is treated in the followingmanner. 1) When R^(13a) is alkyl, etc., the starting compound is reactedwith an acid chloride such as 1-chloroethyl chloroformate or vinylchloroformate optionally in a solvent. Next, an appropriate alcoholicsolvent is added thereto and reacted therewith. Alternatively, it istreated with an appropriate solvent containing hydrochloric acid orhydrobromic acid and then heated in an alcoholic solvent. 2) WhenR^(13a) is tert-butoxycarbonyl, etc., the starting compound is reactedwith an appropriate acid such as acetic acid, trifluoroacetic acid orhydrochloric acid optionally in an appropriate solvent such asdichloromethane or tetrahydrofuran. 3) When R^(13a) is a protectivegroup which can be eliminated, such as benzyl, the starting compound ishydrogenated in an appropriate solvent such as methanol, ethanol, ethylacetate or tetrahydrofuran by using a metal catalyst such as palladiumor platinum (IV) oxide under normal to elevated hydrogen pressure. Thus,a compound represented by the formula (139) can be obtained.

[Step X]

The compound represented by the formula (139) is treated with a haliderepresented by the formula (140) in a solvent in the presence of anappropriate base such as anhydrous potassium carbonate orN,N-diisopropylamine to thereby give a compound represented by theformula (141). As the solvent, use can be made of dryN,N-dimethylformamide, etc. The reaction can be effected at atemperature of 50 to 150° C.

[Step IX]

The compound represented by the formula (141) is treated in thefollowing manner. 1) When R^(13b) is alkyl, etc., the starting compoundis reacted with an acid chloride such as 1-chloroethyl chloroformate orvinyl chloroformate optionally in a solvent. Next, an appropriatealcoholic solvent is added thereto and reacted therewith. Alternatively,it is treated with an appropriate solvent containing hydrochloric acidor hydrobromic acid and then heated in an alcoholic solvent. 2) WhenR^(13a) is tert-butoxycarbonyl, etc., the starting compound is reactedwith an appropriate acid such as acetic acid, trifluoroacetic acid orhydrochloric acid optionally in an appropriate solvent such asdichloromethane or tetrahydrofuran. 3) When R^(13a) is a protectivegroup which can be eliminated, such as benzyl, the starting compound ishydrogenated in an appropriate solvent such as methanol, ethanol, ethylacetate or tetrahydrofuran by using a metal catalyst such as palladiumor platinum (IV) oxide under normal to elevated hydrogen pressure. Thus,a compound represented by the formula (142) can be obtained.

wherein R^(13a), A³ and M are each as defined above; L¹ representsoptionally substituted lower alkyl, trifluoromethyl, optionallysubstituted aryl or optionally substituted heteroaryl; R^(k) and R^(l)may be the same or different and each represents hydrogen or optionallysubstituted lower C₁₋₁₀ alkyl optionally having a heteroatom ; R^(j)represents hydrogen, lower alkyl, amino or protected carboxy; and V¹represents nitrile or methanesulfonyl.

[Step XXXXVI]

An amine represented by the formula (137) is reacted with a carboxylicanhydride, a carboxylic phosphoric anhydride or an acid halideoptionally in an appropriate solvent in the presence of an appropriatebase such as pyridine, triethylamine or N,N-diisopropylethylamine tothereby give an amide represented by the formula (146). As the solvent,use can be made of dry dichloromethane, etc. The reaction can be carriedout at 0° C. to the reflux temperature.

[Step XXXXVII]

The amine represented by the formula (137) is reacted withmethanesulfonic anhydride or an acid halide optionally in an appropriatesolvent such as dichloromethane in the presence of an appropriate basesuch as pyridine, triethylamine or N,N-diisopropylamine to thereby givea compound represented by the formula (145).

[Step XXXXVIII]

The amine represented by the formula (137) is treated with anappropriate sulfamic acid halide optionally in an appropriate solventsuch as dichloromethane in the presence of an appropriate base such aspyridine, triethylamine or N,N-diisopropylethylamine. Alternatively, itis treated with an activated sulfamic acid ester under reflux in asolvent such as 1,4-dioxane. Alternatively, it is reacted with sulfamidein dimethoxyethane at 100° C. Thus, the compound represented by theformula (144) can be obtained.

[Step XXXXIX]

The amine represented by the formula (137) is reacted with anappropriate imidate or thioimidate in a solvent such as acetonitrile ormethanol to thereby give a compound represented by the formula (143). Itis preferable that the reaction is carried out at 0 to 40° C.

wherein M, R^(13a), A³ and R⁴ are each as defined above.

[Step L]

A compound represented by the formula (137) is treated with ethylisocyanatoacetate in an appropriate solvent to thereby give a compoundrepresented by the formula (148). As the solvent, use can be made oftetrahydrofuran, etc. The reaction can be effected at room temperatureto the reflux temperature of the solvent.

wherein M, T, L¹, R^(13a), A³ and R^(a) are each as defined above.

[Step XXXXVI]

An amine represented by the formula (149) is reacted with an activatedester such as a carboxylic anhydride, a carboxylic phosphoric anhydrideor an acid halide optionally in an appropriate solvent in the presenceof an appropriate base such as pyridine, triethylamine orN,N-diisopropylethylamine to thereby give an amide represented by theformula (150). As the solvent, use can be made of dry dichloromethane,etc. The reaction can be carried out at 0° C. to the reflux temperature.

[Step XXI]

The compound represented by the formula (149) is treated with anappropriate alkyl halide having a carboxyl group or an ester group inthe presence of an appropriate base such as pyridine, triethylamine orN,N-diisopropylamine in a solvent such as dichloromethane,tetrahydrofuran or N,N-dimetyl formamide to thereby give an aminecompound represented by the formula (151).

[Step XXXXVII]

The amine represented by the formula (149) is reacted with anappropriate sulfonic anhydride or an acid halide optionally in anappropriate solvent such as dichloromethane in the presence of anappropriate base such as pyridine, triethylamine or N,N-diisopropylamineto thereby give a compound represented by the formula (152).

wherein T, L¹, R^(13a), A³, V¹, R^(j) and R^(a) are each as definedabove.

[Step XXXXVI]

An amine represented by the formula (153) is reacted with a carboxylicanhydride, a carboxylic phosphoric anhydride or an acid halideoptionally in an appropriate solvent in the presence of an appropriatebase such as pyridine, triethylamine or N,N-diisopropylethylamine tothereby give an amide represented by the formula (154). As the solvent,use can be made of dry dichloromethane, etc. The reaction can be carriedout at 0° C. to the reflux temperature.

[Step XXI]

The compound represented by the formula (153) is treated with anappropriate alkyl halide having a carboxyl group or an ester group inthe presence of an appropriate base such as pyridine, triethylamine orN,N-diisopropylamine in a solvent such as dichloromethane,tetrahydrofuran or N,N-dimethylformamide to thereby give an aminecompound represented by the formula (155).

[Step XXXXVII]

The amine represented by the formula (153) is reacted with anappropriate sulfonic anhydride or an acid halide optionally in anappropriate solvent such as dichloromethane in the presence of anappropriate base such as pyridine, triethylamine or N,N-diisopropylamineto thereby give a compound represented by the formula (156).

[Step XXXXIX]

The amine represented by the formula (153) is reacted with anappropriate imidate or thioimidate in a solvent such as acetonitrile ormethanol to thereby give a compound represented by the formula (157). Itis preferable that the reaction is carried out at 0 to 40° C.

wherein G, Z, E, X¹, l¹, M, R^(13a), A³ and Hal are each as definedabove.

[Step XXXXVII]

An amine represented by the formula (137) is reacted with an appropriatesulfonic acid halide derivative in an appropriate dry solvent such asdichloromethane or diethyl ether to thereby give a compound representedby the formula (158). The reaction is effected preferably at 0° C. toroom temperature.

[Step IX]

The compound represented by the formula (158) is subjected to areduction reaction with the use of an appropriate metal catalyst in asolvent to thereby give a compound represented by the formula (159). Forexample, the reaction may be effected in a solvent such as methanol,ethanol, ethyl acetate or tetrahydrofuran with the use of palladium orplatinum (IV) oxide as a catalyst under normal to elevated hydrogenpressure.

[Step X]

The compound represented by the formula (159) is treated with a haliderepresented by the formula (133) in a solvent in the presence of anappropriate base such as anhydrous potassium carbonate orN,N-diisopropylamine to thereby give a compound represented by theformula (160). As the solvent, use can be made of dryN,N-dimethylformamide, etc. The reaction can be effected at atemperature of 50 to 150° C.

[Step LI]

The compound represented by the formula (160) is treated with a reagentsuch as tetra-n-butylammonium fluoride or caesium fluoride in a drysolvent such as tetrahydrofuran to thereby give a carboxylic acidrepresented by the formula (161). The reaction is effected preferably at0° C. to room temperature.

wherein M, T, R^(13a), A³ and R^(a) are each as defined above; and Nurepresents a nucleophilic atom such as oxygen, nitrogen or sulfur.

[Step XXI]

A compound represented by the formula (162) is treated with anappropriate alkyl halide having a carboxyl group or an ester groupeither in a solvent such as dichloromethane, tetrahydrofuran orN,N-dimethylformamide in the presence of an appropriate base such aspyridine, triethylamine or N,N-diisopropylamine, or after being treatedwith a base such as sodium hydride or sodium methoxide in a solvent suchas dimethoxyethane, tetrahydrofuran or N,N-dimethylformamide to therebygive a derivative represented by the formula (163). When Nu is oxygenand a phenol derivative is employed as a substitute for the alkylhalide, an ether represented by the formula (163) can be obtained by theMitsunobu reaction with the use of a condensing agent such as diethylazadicarboxylate or triphenylphosphine.

[Step LII]

The compound represented by the formula (162) is reacted with sodiumisocyanate, potassium isocyanate, etc. in a solvent such as water orethanol to thereby give a compound represented by the formula (164).

wherein M, R^(13a), A⁷, R^(s) and R^(t) are each as defined above.

[Step XXIX]

A solution of a compound represented by the formula (165) in, forexample, methylene chloride is added to a reaction mixture obtained fromoxalyl chloride and dimethyl sulfoxide and treated with a base such astriethylamine. Alternatively, it is treated with pyridinium dichromatein a solvent such as dichloromethane or treated with manganese dioxidein a solvent such as dichloromethane. Thus, a carbonyl compoundrepresented by the formula (166) can be obtained.

[Step XXIV]

A compound represented by the formula (171) is treated with a reducingagent such as diisobutylaluminum hydride, aluminum lithium hydride orlithium borohydride in a solvent such as dry tetrahydrofuran or drydiethyl ether, or treated with a reducing agent such as sodiumborohydride in an alcoholic solvent to thereby give an alcoholrepresented by the formula (172).

[Step XXXVI]

The compound represented by the formula (169) is treated with bromine inan appropriate alcoholic solvent such as methanol or ethanol in thepresence of a base such as sodium hydrogencarbonate or potassiumcarbonate preferably at 0° C. to room temperature. Alternatively, thestarting compound is treated with pyridinium chromate in an appropriatealcoholic solvent such as methanol or ethanol. Alternatively, it istreated with manganese dioxide in an appropriate alcoholic solvent suchas methanol or ethanol in the presence of sodium cyanide and acetic acidand then treated with sulfuric acid, hydrochloric acid, thionylchloride, etc. in an appropriate alcoholic solvent such as methanol orethanol. Alternatively, it is treated with sodium chlorite in a solventmixture of water and dimethyl sulfoxide in the presence of sodiumdihydrogenphosphate and then reacted with trimethylsilyl-diazomethane ina solvent such as methanol. Alternatively, it is treated with anactivating agent such as thionyl chloride in an appropriate alcoholicsolvent such as methanol or ethanol. Thus, an ester compound representedby the formula (170) can be obtained.

[Step XXIVI]

A compound represented by the formula (167) is treated with a reducingagent such as diisobutylaluminum hydride, aluminum lithium hydride orlithium borohydride in a solvent such as dry tetrahydrofuran or drydiethyl ether to thereby give an alcohol represented by the formula(168).

[Step XVII]

A cyano compound of the formula (173) is treated with a base such assodium hydroxide or potassium hydroxide in an alcoholic solvent such asethanol, propanol, ethylene glycol or diethylene glycol and heated underreflux to thereby give a carboxylic acid of the formula (174).

[Step XVIII]

The compound of the formula (174) is treated with an activator such asthionyl chloride in an alcoholic solvent such as methanol or ethanol tothereby give an ester of the formula (175). The reaction temperaturepreferably ranges from 0° C. to room temperature.

wherein Hal, R^(13a), A³ and R^(d) are each as defined above.

[Step X]

A compound represented by the formula (177) is heated with a amineprotecting reagent such as benzyl chloride in a solvent to thereby givea compound represented by the formula (178). As the solvent, use can bemade of dry N,N-dimethylformamide, acetone, ethanol, etc. The reactioncan be effected at a temperature of 50° C. to the reflux temperature.

[Step XXIV]

The compound represented by the formula (178) is treated with a reducingagent such as lithium borohydride in a solvent to thereby give acompound represented by the formula (179). As the solvent, use can bemade of dry N,N-dimethylformamide, acetone, ethanol, etc. The reactioncan be effected at 50° C. to the reflux temperature.

[Step VIII]

The compound represented by the formula (179) is treated optionally inan appropriate solvent such as dichloromethane or tetrahydrofuran/waterin the presence of an appropriate acid such as acetic acid,trifluoroacetic acid or hydrochloric acid to thereby give a compoundrepresented by the formula (180). The reaction can be effected at 0° C.to the reflux temperature of the solvent.

wherein M, R^(13a), A³ and R^(a) are each as defined above.

[Step LIII]

A ketone represented by the formula (176) is reacted with an anionobtained by treating an alkyne with a strong base such as n-butyllithiumor lithium diisopropylamine in a dry solvent such as tetrahydrofuran ordiethyl ether to thereby give a compound represented by the formula(181). The reaction can be effected at −100° C. to room temperature.

[Step XIV]

The compound represented by the formula (181) is subjected to areduction reaction in a solvent with the use of an appropriate metalcatalyst to thereby give a compound represented by the formula (182).For example, use can be made of a hydrogenation reaction effected in asolvent such as methanol, ethanol, ethyl acetate or tetrahydrofuran withthe use of palladium, platinum (IV) oxide, etc. under normal to elevatedhydrogen pressure.

[Step XXXXI]

A compound represented by the formula (147) is treated withmethyllithium or methylmagnesium halide in a solvent such as drytetrahydrofuran, diethyl ether or dimethoxyethane at −78° C. to theboiling point of the solvent to thereby give an alcohol represented bythe formula (183).

wherein M, R^(13a), A³ and R^(a) are each as defined above; and X_(n)means an alkylene side chain having n carbon atoms which is directlybonded to the ring when n is 0.

[Step LIV]

A compound of the formula (184) is reacted with dimethyl malonate in asolvent such as pyridine at room temperature to the boiling point of thesolvent. Then the intermediate thus obtained is treated withdiazomethane in a solvent to thereby give a compound represented by theformula (185).

wherein M, R^(13a), A³, X_(n) and R^(a) are each as defined above.

[Step LV]

An aldehyde represented by the formula (184) is treated with carbontetrabromide and a phosphine such as triphenylphosphine in a solventsuch as dry dichloromethane to thereby give a dibromoalkene derivativerepresented by the formula (186).

[Step LVI]

The compound represented by the formula (186) is treated with a strongbase such as n-butyllithium in a dry solvent such as tetrahydrofuran ordiethyl ether at −100 to 0° C. Then the intermediate thus obtained istreated with a reagent such as ethyl chloroformate or diethyl carbonateto thereby give a compound represented by the formula (187).

wherein M, R^(13a), A³, X_(n) and R^(a) are each as defined above.

[Step XV]

The compound represented by the formula (188) is reacted with a strongbase such as lithium diisopropylamide in a dry solvent such astetrahydrofuran, diethyl ether or hexamethylphosphorous triamide at −100to 0° C. and then reacted with a dihalogenated ethane such asdibromoethane to thereby give a derivative represented by the formula(189).

[Step LVII]

The compound represented by the formula (189) is treated with potassiumtert-butoxide in a dry solvent such as tetrahydrofuran to thereby give acyclopropyl derivative represented by the formula (190). The reactioncan be effected at 0° C. to the reflux temperature of the solvent.

wherein M, R^(13a), A³, and R^(a) are each as defined above.

[Step LVIII]

A compound represented by the formula (188) is treated with a strongbase such as n-butyllithium or lithium diisopropylamide in a dry solventsuch as tetrahydrofuran, diethyl ether or hexamethyl-phosphoroustriamide at −100 to 0° C. and then treated with peroxymolybdeum(pyridine) hexamethylphosphorous triamide to thereby give a compoundrepresented by the formula (191).

wherein M, R^(13a), A⁷, R^(d), R^(k) and R^(a) are each as definedabove.

[Step XV]

A compound represented by the formula (192) is treated with a strongbase such as lithium diisopropylamide in a dry solvent such astetrahydrofuran, diethyl ether or hexamethylphosphorous triamide at −100to 0° C. and then reacted with an alkylating agent such as methyl iodideto thereby give a derivative represented by the formula (193).

[Step XXIV]

The compound represented by the formula (193) is treated with a reducingagent such as diisobutylaluminum hydride, aluminum lithium hydride orlithium borohydride in a solvent such as dry tetrahydrofuran or drydiethyl ether to thereby give an alcohol represented by the formula(194).

[Step XXVIII]

The alcohol represented by the formula (194) is reacted withmethanesulfonyl chloride, p-toluenesulfonyl chloride etc. in thepresence of an appropriate base such as pyridine. Next, it is treatedwith a cyanidation agent such as sodium cyanide or potassium cyanide inan aprotic polar solvent such as dimethyl sulfoxide orN,N-dimethylformamide to thereby give a cyano compound represented bythe formula (195). This reaction can be effected at room temperature tothe boiling point of the solvent.

[Step IX]

The compound represented by the formula (195) is treated in thefollowing manner. 1) When R^(13a) is alkyl, etc., the starting compoundis reacted with an acid chloride such as 1-chloroethyl chloroformate orvinyl chloroformate optionally in a solvent. Next, an appropriatealcoholic solvent is added thereto and reacted therewith. Alternatively,it is treated with an appropriate solvent containing hydrochloric acidor hydrobromic acid and then heated in an alcoholic solvent. 2) WhenR^(13a) is tert-butoxycarbonyl, etc., the starting compound is reactedwith an appropriate acid such as acetic acid, trifluoroacetic acid orhydrochloric acid optionally in an appropriate solvent such asdichloromethane or tetrahydrofuran. 3) When R^(13a) is a protectivegroup which can be eliminated, such as benzyl, the starting compound ishydrogenated in an appropriate solvent such as methanol, ethanol, ethylacetate or tetrahydrofuran by using a metal catalyst such as palladiumor platinum (IV) oxide under normal to elevated hydrogen pressure. Thus,a compound represented by the formula (196) can be obtained.

[Step XXXIII]

A compound represented by the formula (196) is reacted with, forexample, benzyl chloride as an amino protective group preferably at 0°C. to room temperature in the presence of a base such as pyridine,triethylamine or N,N-diisopropylethylamine in an appropriate solventsuch as methanol or dichloromethane to thereby give a compoundrepresented by the formula (197). R^(13b) may be an arbitrary one, solong as it is lower alkyl or an amino protective group. The mostdesirable example of R^(13b) is benzyl.

wherein M, R^(13a), A³ and R^(a) are each as defined above.

[Step LIX]

The compound represented by the formula (198) is reacted with ethylvinyl ether preferably at 0° C. to room temperature without using anysolvent in the presence of a mercuric salt to thereby give an etherrepresented by the formula (199). Mercuric trifluoroacetate is the mostdesirable catalyst.

[Step LX]

The compound represented by the formula (199) is heated in anappropriate solvent to thereby give an aldehyde represented by theformula (200). As the solvent, use can be made of benzonitrile, decalin,nitrobenzene, etc. The reaction can be effected at 100° C. to the refluxtemperature.

[Step XXXVI]

The compound represented by the formula (200) is treated with pyridiniumdichromate in an appropriate alcoholic solvent such as methanol orethanol to thereby give an ester represented by the formula (201).

[Step XIV]

The compound represented by the formula (201) is subjected to areduction reaction in a solvent with the use of an appropriate metalcatalyst to thereby give a compound represented by the formula (202).For example, use can be made of a hydrogenation reaction effected in asolvent such as methanol, ethanol, ethyl acetate or tetrahydrofuran withthe use of palladium, platinum (IV) oxide, etc. under nor

wherein M, R^(13a), A³, R^(d) and R^(a) are each as defined above; andB² represents hydrogen, lower alkyl, lower alkoxy or halide.

[Step LXI]

A compound represented by the formula (176) is subjected in anappropriate solvent to a halogen-metal exchange reaction or reacted withan aryl-Grignard or aryllithium obtained by a lithiation reaction tothereby give a compound represented by the formula (203). As thesolvent, use can be made of a dry solvent such as tetrahydrofuran,diethyl ether or dimethoxyethane. The reaction can be effected at −100°C. to the reflux temperature of the solvent.

[Step VIII]

The compound represented by the formula (203) is treated optionally inan appropriate solvent such as dichloromethane or tetrahydrofuran/waterwith an appropriate acid such as acetic acid, trifluoroacetic acid orhydrochloric acid to thereby give a compound represented by the formula(204). The reaction can be effected at 0° C. to the reflux temperatureof the solvent.

[Step XXIII]

The aldehyde represented by the formula (204) is reacted with an anionobtained by treating a dithiane such as 2-trimethyl-1,3-dithiane with astrong base such as butyllithium at −100° C. to room temperature in adry solvent such as tetrahydrofuran. The dithiane thus obtained is thentreated with a metal salt such as mercury chloride in a solvent such asmethanol/water. Alternatively, it is reacted with methylmethylsulfinylmethyl sulfoxide in a solvent such as methanol at roomtemperature to the reflux temperature in the presence ofbenzyltrimethylammonium hydroxide and the intermediate thus obtained istreated under acidic conditions with the use of, for example, hydrogenchloride/methanol to thereby give an ester represented by the formula(205).

wherein M, R^(13a), R^(13b), A³, B² and R^(a) are each as defined above;and R^(pa) represents a hydroxy protective group such as benzyl ormethoxymethyl, or hydrogen.

[Step LXI]

The compound represented by the formula (176) is subjected in anappropriate solvent to a halogen-metal exchange reaction or reacted withan aryl-Grignard or aryllithium obtained by a hydrogen-metal exchangereaction to thereby give compounds represented by the formulae (207),(211) and (215). As the solvent, use can be made of a dry solvent suchas tetrahydrofuran, diethyl ether or dimethoxyethane. The reaction canbe effected at −100° C. to the reflux temperature of the solvent.

[Step LXVII]

The compounds represented by the formulae (207), (211) and (215) aresubjected to a dehydration reaction by heating under reflux in thepresence of an acid catalyst in an appropriate solvent to thereby givecompounds represented by the formulae (208), (212) and (216)respectively. As the solvent, use can be made of benzene, toluene, etc.

[Step XIV]

The compounds represented by the formulae (208), (213) and (216) aresubjected to a reduction reaction with the use of an appropriate metalcatalyst to thereby give compounds represented by the formulae (209),(214) and (217) respectively. The reaction may be carried out in, forexample, a solvent such as methanol, ethanol, ethyl acetate ortetrahydrofuran under normal to elevated hydrogen pressure with the useof palladium, platinum (IV) oxide, etc. as the catalyst.

[Step XXXIII]

The compounds represented by the formulae (209) and (217) are reactedwith, for example, di-tert-butyl dicarbonate as an amino protectivegroup preferably at 0° C. to room temperature in the presence of a basesuch as pyridine, triethylamine or N,N-diisopropylethylamine in anappropriate solvent such as methanol or dichloromethane to thereby givecompounds represented by the formulae (210) and (218). R^(13b) may be anarbitrary one, so long as it is lower alkyl or an amino protectivegroup. The most desirable example of R^(13b) is alkyl carbamate.

[Step LXIII]

The compound represented by the formula (212) is treated withn-butyllithium in a dry solvent such as tetrahydrofuran at −100 to 0° C.and the anion thus obtained is treated with a regent such as diethylcarbonate or ethyl chloroformate to thereby give a compound representedby the formula (213).

wherein R^(13a), A⁷, B², R^(s) and R^(t) are each as defined above.

[Step LXIV]

A compound represented by the formula (219) is reacted with anappropriate benzyl cyanide in the presence of an appropriate phasetransfer catalyst in a thick aqueous solution of an alkali to therebygive a piperidine derivative represented by the formula (220). Thisreaction can be effected at room temperature to 100° C.

wherein R^(13a), A³, R^(k), R^(s) and R^(t) are each as defined above.

[Step LXV]

A carbonyl derivative represented by the formula (221) is reacted withan appropriate hydroxylamine in a solvent such as ethanol in thepresence of a catalyst such as sodium acetate to thereby give an oximerepresented by the formula (222). This reaction can be effected at roomtemperature to the reflux temperature.

[Step XXI]

The oxime represented by the formula (222) is treated with a base suchas sodium hydride or sodium methoxide and then reacted with an alkylhalide in a solvent such as dimethoxyethane, tetrahydrofuran orN,N-dimethylformamide to thereby give a derivative represented by theformula (223). This reaction is effected preferably at 0° C. to roomtemperature.

[Step LXVI]

An α,β-unsaturated ester represented by the formula (224) is treatedwith a base such as 1,8-diazabicyclo[5.4.0]-7-undecene at roomtemperature to reflux temperature in an appropriate solvent such astoluene to thereby give a β,γ-derivative represented by the formula(225). mal to elevated hydrogen pressure.

wherein M, R^(13a), A⁷, R^(a), R^(d), R^(k), R^(s) and R^(t) are each asdefined above.

[Step XXXII]

Methyltriphenylphosphonium bromide is treated with an appropriate basesuch as potassium tert-butoxide or butyllithium in a solvent such astoluene, xylene or tetrahydrofuran. Next, ketones represented by theformulae (167) and (228) are reacted therewith to thereby give compoundsrepresented by the formulae (226) and (229) respectively. The reactiontemperature preferably ranges from −78° C. to room temperature.

[Step XXXIV]

The compound represented by the formula (226) is treated withzinc/copper alloy and trichloroacetyl chloride in a dry solvent such asdiethyl ether, dimethoxyethane or tetrahydrofuran to thereby give acrude dichlorobutyl ketone derivative represented by the formula (227).The reaction temperature preferably ranges from 0 to 50° C.

[Step LXVII]

The dichloroketone represented by the formula (227) is treated with areducing agent such as zinc in an alcoholic solvent such as methanol inthe presence of ammonium chloride to thereby give a ketone compoundrepresented by the formula (228). The reaction temperature preferablyranges from 0 to 50° C.

[Step XXXV]

An exo-methylene compound represented by the formula (229) is treatedwith an appropriate borane compound such as a borane/tetrahydrofurancomplex in an appropriate solvent such as dry tetrahydrofuran ordimethoxyethane followed by the treatment with an oxidizing agent suchas hydrogen peroxide in an alkali solution to thereby give an alcoholcompound represented by the formula (230).

[Step XIII]

The compound represented by the formula (228) is reacted with anappropriate Horner-Emmons reagent in a solvent in the presence of anappropriate base to thereby give a compound represented by the formula(231). As the solvent, use can be made of dry solvents such asN,N-dimethylformamide, tetrahydrofuran or diethyl ether. As the base,use can be made of sodium hydride, potassium tert-butoxide,n-butyllithium, lithium diisopropylamide, etc. The reaction can beeffected at −100° C. to the reflux temperature of the solvent.

[Step LXVIII]

The α,β-unsaturated ester represented by the formula (231) is reactedwith an alkylcopper complex in a dry solvent such as diethyl ether inthe presence of an appropriate activator such as chlorotrimethylsilaneto thereby give a compound represented by the formula (232). Thereaction is effected preferably at −80 to 0° C.

[Step XVI]

The compound represented by the formula (228) is treated with acyanidation reagent such as tosylmethyl isocyanide in a mixture of asolvent such as dimethoxyethane, tetrahydrofuran or diethyl ether withan alcoholic solvent such as tert-butanol in the presence of a base suchas potassium tert-butoxide to thereby give a cyano compound representedby the formula (233). It is preferable to effect this reaction at atemperature of 0 to 100° C.

[Step IX]

The compound represented by the formula (233) is treated in thefollowing manner. 1) When R^(13a) is alkyl, etc., the starting compoundis reacted with an acid chloride such as 1-chloroethyl chloroformate orvinyl chloroformate optionally in a solvent. Next, an appropriatealcoholic solvent is added thereto and reacted therewith. Alternatively,it is treated with an appropriate solvent containing hydrochloric acidor hydrobromic acid and then heated in an alcoholic solvent. 2) WhenR^(13a) is tert-butoxycarbonyl, etc., the starting compound is reactedwith an appropriate acid such as acetic acid, trifluoroacetic acid orhydrochloric acid optionally in an appropriate solvent such asdichloromethane or tetrahydrofuran. 3) When R^(13a) is a protectivegroup which can be eliminated, such as benzyl, the starting compound ishydrogenated in an appropriate solvent such as methanol, ethanol, ethylacetate or tetrahydrofuran by using a metal catalyst such as palladiumor platinum (IV) oxide under normal to elevated hydrogen pressure. Thus,a compound represented by the formula (234) can be obtained.

[Step XXXIII]

The compound represented by the formula (234) is reacted with, forexample, benzyl chloride as an amino protective group preferably at 0°C. to room temperature in the presence of a base such as pyridine,triethylamine or N,N-diisopropylethylamine in an appropriate solventsuch as methanol or dichloromethane to thereby give a compoundrepresented by the formula (235). R^(13b) may be an arbitrary one, solong as it is lower alkyl or an amino protective group. The mostdesirable example of R^(13b) is benzyl.

wherein M, R^(13a), A³, R^(a), R^(k), R^(s) and R^(t) are each asdefined above.

[Step LXIX]

A ketone compound represented by the formula (236) is treated with aperoxide such as 3-chloroperbenzoic acid in an appropriate solvent suchas dichloromethane in the presence of sodium carbonate, etc. to therebygive a lactone compound represented by the formula (237). The reactiontemperature preferably ranges from −100 to 0° C.

[Step LXX]

The lactone compound represented by the formula (237) is treated withdiisobutylaluminum hydride in an appropriate solvent such as toluene ordichloromethane to thereby give a lactol compound represented by theformula (238). The reaction temperature preferably ranges from −100 to0° C.

[Step XIII]

The compound represented by the formula (238) is reacted with anappropriate Horner-Emmons reagent in a solvent in the presence of anappropriate base to thereby give a compound represented by the formula(239). As the solvent, use can be made of dry solvents such asN,N-dimethylformamide, tetrahydrofuran or diethyl ether. As the base,use can be made of sodium hydride, potassium tert-butoxide,n-butyllithium, lithium diisopropylamide, etc. The reaction can beeffected at −100° C. to the reflux temperature of the solvent.

[Step XIV]

The compound represented by the formula (239) is subjected to areduction reaction with the use of an appropriate metal catalyst in asolvent to thereby give a compound represented by the formula (240). Thereaction may be carried out in, for example, a solvent such as methanol,ethanol, ethyl acetate or tetrahydrofuran under normal to elevatedhydrogen pressure with the use of palladium, platinum (IV) oxide, etc.as the catalyst.

wherein M, R^(13a), A³ and X_(n) are each as defined above.

[Step LXXI]

An alkene compound represented by the formula (241) is reacted withdiethylzinc and iodomethane in an appropriate solvent such asdichloromethane to thereby give a cyclopropyl derivative represented bythe formula (242). The reaction temperature preferably ranges from 0° C.to room temperature.

wherein M, R^(13a) and A³ are each as defined above.

[Step XXXXI]

A compound represented by the formula (176) is treated with allyllithiumor allylmagnesium halide in a solvent such as dry tetrahydrofuran,diethyl ether or dimethoxyethane at −78° C. to the boiling point of thesolvent to thereby give an alcohol represented by the formula (243).

[Step LXXII]

The alkene compound represented by the formula (243) is treated with aperoxide such as 3-chloroperbenzoic acid in an appropriate solvent suchas dichloromethane in the presence of sodium carbonate, etc to therebygive an epoxide represented by the formula (244). The reactiontemperature preferably ranges from room temperature to 40° C.

[Step LXXIII]

The compound represented by the formula (244) is treated with a basesuch as lithium hydroxide in a solvent mixture of dimethyl sulfoxidewith water to thereby give a compound represented by the formula (245).The reaction temperature preferably ranges from 50 to 150° C.

wherein G, Z, E, X¹, l¹, R^(13a), Hal and R^(a) are each as definedabove.

[Step LXXVI]

A thiophene derivative represented by the formula (265) is treated witha strong base such as n-butyllithium or lithium diisopropylamide in adry solvent such as tetrahydrofuran, diethyl ether orhexamethylphosphorous triamide at from −100 to 0° C. Then the anion thusobtained is treated with a formulation agent such asN,N-dimethylformamide to thereby give an aldehyde represented by theformula (266).

[Step LXXVII]

The aldehyde represented by the formula (266) is reacted with an anionobtained by treating a dithiane such as 2-trimethylsilyl-1,3-dithianewith a strong base such as butyllithium in a dry solvent such astetrahydrofuran at from −100° C. to room temperature to thereby give amethylenethiazine represented by the formula (267).

[Step IX]

The compound represented by the formula (267) is treated with anappropriate acid such as hydrochloric acid, trifluoroacetic acid oracetic acid optionally in an appropriate solvent such as dichloromethaneor tetrahydrofuran to thereby give an amine represented by the formula(268).

[Step X]

The compound represented by the formula (267) is treated with a haliderepresented by the formula (140) in a solvent in the presence of anappropriate base such as anhydrous potassium carbonate orN,N-diisopropylethylamine to thereby give a compound represented by theformula (269). As the solvent, use can be made of dryN,N-dimethylformamide, etc. The reaction can be effected at from 0 to150° C.

[Step LXXVIII]

The methylenethiazine represented by the formula (269) is treated with ametal salt such as mercury chloride in a solvent such as methanol/waterto thereby give an ester compound represented by the formula (270).

wherein G, Z, E, X¹, l¹, R′, R^(a) and Hal are each as defined above.

[Step X]

A compound represented by the formula (131) is treated with a protected3-(hydroxymethyl)pyridine derivative in a solvent in the presence of anappropriate base such as anhydrous potassium carbonate orN,N-diisopropylethylamine to thereby give a compound represented by theformula (271). As the solvent, use can be made of dryN,N-dimethylformamide, etc. The reaction can be effected at from 0 to150° C.

[Step XXIV]

The compound represented by the formula (271) is treated with a reducingagent such as sodium borohydride in a solvent to thereby give a compoundrepresented by the formula (272). As the solvent, use can be made ofmethanol, ethanol, etc. The reaction can be effected at from 0° C. tothe reflux temperature.

[Step LI]

The compound represented by the formula (272) is treated with a reagentsuch as tetra-n-butylammonium fluoride or caesium fluoride in a drysolvent such as tetrahydrofuran to thereby give an alcohol representedby the formula (273). The reaction is effected preferably at from 0° C.to room temperature.

[Step XXIX]

A solution of the alcohol represented by the formula (273) in, forexample, methylene chloride is added to a reaction mixture obtained fromoxalyl chloride and dimethyl sulfoxide and treated with a base such astriethylamine. Alternatively, it is treated with pyridinium dichromatein a solvent such as dichloromethane or N,N-dimethylformamide or treatedwith manganese dioxide in a solvent such as dichloromethane. Thus, analdehyde represented by the formula (274) can be obtained.

[Step XXXVI]

The compound represented by the formula (274) is treated with bromine inan appropriate alcoholic solvent such as methanol or ethanol in thepresence of a base such as sodium hydrogencarbonate or potassiumcarbonate preferably at from 0° C. to room temperature. Alternatively,the starting compound is treated with pyridinium chromate in anappropriate alcoholic solvent such as methanol or ethanol.Alternatively, it is treated with manganese dioxide in an appropriatealcoholic solvent such as methanol or ethanol in the presence of sodiumcyanide and acetic acid and then treated with sulfuric acid,hydrochloric acid, thionyl chloride, etc. in an appropriate alcoholicsolvent such as methanol or ethanol. Alternatively, it is treated withsodium chlorite in a solvent mixture of water with dimethyl sulfoxide inthe presence of sodium dihydrogenphosphate and then reacted withtrimethylsilyl-diazomethane in a solvent such as methanol.Alternatively, it is treated with an activating agent such as thionylchloride in an appropriate alcoholic solvent such as methanol orethanol. Thus, an ester compound represented by the formula (275) can beobtained.

wherein G, Z, A¹, E, X¹, l¹, Hal and R′ are each as defined above.

[Step LXXIX]

4-Hydroxypyridine is treated with a strong base such as sodium hydrideor lithium diisopropylamide in a dry solvent such as tetrahydrofuran orN,N-dimethylformamide. The anion thus obtained is then treated with ahalogen compound (131) at from 0 to 100° C. to thereby give a pyridonerepresented by the formula (277).

[Step XXIV]

The pyridone represented by the formula (277) is treated with a reducingagent such as aluminum lithium hydride in a dry solvent such as drydiethyl ether at from 0 to 50° C. to thereby give an α,β-unsaturatedenone (278).

wherein G, Z, R^(a), E, X¹, l¹, Hal and R′ are each as defined above.

[Step LXXIX]

The compound represented by the formula (279) is treated with a strongbase such as sodium hydride or lithium diisopropylamide in a dry solventsuch as tetrahydrofuran or N,N-dimethylformamide. The anion thusobtained is then treated with a halogen compound (131) at from 0 to 100°C. to thereby give a compound represented by the formula (280).

[Step VIII]

The compound represented by the formula (280) is treated with anappropriate acid such as hydrochloric acid, trifluoroacetic acid oracetic acid optionally in an appropriate solvent such as dichloromethaneor tetrahydrofuran to thereby give an amine represented by the formula(281).

[Step LXXX]

The ester compound represented by the formula (281) is treated withwater and an excessive amount of a strong base such as potassiumtert-butoxide in a dry solvent such as dimethyl sulfoxide to therebygive a carboxylic acid represented by the formula (282). This reactionis effected preferably at from 0 to 50° C.

wherein A³, G, Z, R^(a), E, X¹, l¹, Hal and R′ are each as definedabove.

[Step XI]

A compound represented by the formula (283) is treated with anappropriate base in an aqueous ethanol solvent followed by hydrolysis tothereby give a compound having a carboxyl group represented by theformula (284). As the base, use can be made of sodium hydroxide,potassium hydroxide, etc. The reaction can be effected at from roomtemperature to the reflux temperature of the solvent.

wherein G, Z, M, E, X¹, l¹, Hal, A³ and R′ are each as defined above.

[Step XXXXVI]

An amine represented by the formula (137) is reacted with diketen in anappropriate solvent to thereby give an amdie represented by the formula(285). As the solvent, use can be made of toluene, etc. The reaction canbe effected at from 0° C. to the reflux temperature.

[Step IX]

The compound represented by the formula (285) is subjected to areduction reaction in a solvent with the use of an appropriate metalcatalyst to thereby give a compound represented by the formula (286).The reaction may be carried out in, for example, a solvent such asmethanol, ethanol, ethyl acetate or tetrahydrofuran under normal toelevated hydrogen pressure with the use of palladium, platinum (IV)oxide, etc. as the catalyst.

[Step X]

The compound represented by the formula (286) is treated with a haliderepresented by the formula (131) in a solvent in the presence of anappropriate base such as anhydrous potassium carbonate orN,N-diisopropylethylamine to thereby give a compound represented by theformula (287). As the solvent, use can be made of dryN,N-dimethylformamide, etc. The reaction can be effected at from 0 to150° C.

[Step LXXXI]

The dicarbonyl compound represented by the formula (287) is treated withN,N-dimethylformamide dimethyl acetal in an appropriate solvent at from50 to 100° C. to thereby give a compound represented by the formula(288).

[Step LXXXII]

The compound represented by the formula (288) is reacted withhydroxylamine hydrochloride in an alcoholic solvent such as methanol atfrom room temperature to the reflux temperature to thereby give anoxazole represented by the formula (289).

[Step VIII]

The compound represented by the formula (289) is treated with anappropriate acid such as hydrochloric acid, trifluoroacetic acid oracetic acid optionally in an appropriate solvent such as dichloromethaneor tetrahydrofuran to thereby give an amine represented by the formula(290).

[Step LXXXIII]

The isoxazole represented by the formula (290) is treated withN,N-dimethylformamide dimethyl acetal in a dry solvent such astetrahydrofuran at from room temperature to the reflux temperature tothereby give a compound represented by the formula (291).

wherein G, Z, E, X¹, l¹, A¹, R^(k) and R^(l) are each as defined above.

[Step LXXXIV]

An amine represented by the formula (292) is reacted with3,4-dimethoxy-3-cyclobutene-1,2-dione in an appropriate solvent such asN,N-dimethylformamide, ethanol, methanol or dichloromethane optionallyin the presence of a base such as triethylamine at from room temperatureto the reflux temperature to thereby give a compound represented by theformula (293).

[Step LXXXIV]

The compound represented by the formula (293) is treated with anappropriate amine or ammonia in an appropriate solvent such asN,N-dimethylformamide, ethanol, methanol or dichloromethane optionallyin the presence of a base such as triethylamine at from room temperatureto the reflux temperature to thereby give a compound represented by theformula (294).

wherein R^(l3a), R^(k) and R^(l) are each as defined above.

[Step LXXXIV]

An amine represented by the formula (153) is reacted with3,4-dimethoxy-3-cyclobutene-1,2-dione in an appropriate solvent such asN,N-dimethylformamide, ethanol, methanol or dichloromethane optionallyin the presence of a base such as triethylamine at from room temperatureto the reflux temperature to thereby give a compound represented by theformula (295).

[Step LXXXIV]

The compound represented by the formula (295) is treated with anappropriate amine or ammonia in an appropriate solvent such asN,N-dimethylformamide, ethanol, methanol or dichloromethane optionallyin the presence of a base such as triethylamine at from room temperatureto the reflux temperature to thereby give a compound represented by theformula (296).

wherein G, Z, E, X¹, l¹, A³, R′, R^(d), X_(n) and V¹ are each as definedabove.

[Step X]

A compound represented by the formula (297) is treated with a haliderepresented by the formula (131) in a solvent in the presence of anappropriate base such as anhydrous potassium carbonate orN,N-diisopropylethylamine to thereby give a compound represented by theformula (298). As the solvent, use can be made of dryN,N-dimethylformamide, etc. The reaction can be effected at from 0 to150° C.

[Step VIII]

The compound represented by the formula (298) is treated with anappropriate acid such as hydrochloric acid, trifluoroacetic acid oracetic acid optionally in an appropriate solvent such as dichloromethaneor tetrahydrofuran to thereby give an amine represented by the formula(299).

[Step LXXXV]

The nitrile compound represented by the formula (299) is treated with anappropriate acid in an alcoholic solvent to thereby give an imidaterepresented by the formula (300) (i.e., the so-called Pinner reaction).It is preferable to use hydrochloric acid as the acid. The reaction ispreferably effected in methanol at from 0 to 10° C.

[Step LXXXVI]

The imidate represented by the formula (300) is reacted with an amine oran amide in an appropriate solvent to thereby give a compoundrepresented by the formula (301). The most desirable solvent isacetonitrile. The reaction is effected preferably at from roomtemperature to 40° C.

[Step LXXXVII]

The nitrile represented by the formula (298) is treated with anazidation agent such as sodium azide in a dry solvent such as dimethylsulfoxide, N,N-dimethylformamide or 1-methyl-2-pyrrolidone at from 50°C. to the reflux temperature in the presence of a catalyst such asammonium chloride to thereby give a tetrazole derivative represented bythe formula (302).

wherein G, Z, E, X¹, l¹, R^(k), R^(l) and Hal are each as defined above;A⁸ represents heteroaryl having no acidic proton group such as NH; and ψrepresents lower alkyl or oxygen.

[Step X]

A halogen compound represented by the formula (140) is treated with aheteroaryl compound having no acidic proton, such as pyridine, an aminecompound represented by the formula (305), a tertiary amine or anN,N-dialkylhydroxylamine, to thereby give compounds represented by theformulae (303), (306) and (307) respectively. As the solvent, use can bemade of ethanol, dry N,N-dimethylformamide, etc. The reaction can beeffected at from 50 to 150° C.

[Step LXXXVIII]

A carboxylic acid represented by the formula (304) is reacted with asilylation agent such as chlorotrimethylsilane, trimethylsilyltrifluoroacetate or N-methyl-N-(trimethylsilyl)trifluoroacetamide in anappropriate solvent optionally in the presence of a base such asimidazole, pyridine or N,N-diisopropylethylamine to thereby give anester compound represented by the formula (305). As the solvent, use canbe made of dry solvent such as N,N-dimethylformamide, acetonitrile ordichloromethane. The reaction can be effected at from 0 to 40° C.

wherein A³, M, R^(k) and R^(l) are each as defined above.

[Step LXXXIX]

An acid halide represented by the formula (308) is treated with anappropriate amine optionally in an appropriate solvent suchdichloromethane or methanol in the presence of an appropriate base suchas pyridine, triethylamine or N,N-diisopropylethylamine to thereby givea compound represented by the formula (309).

[Step XIV]

The compound represented by the formula (309) is subjected to areduction reaction with the use of an appropriate metal catalyst in asolvent to thereby give a compound represented by the formula (310). Thereaction may be carried out in, for example, a solvent such as methanol,ethanol, ethyl acetate or tetrahydrofuran with the use of palladium,platinum (IV) oxide, etc. as the catalyst under normal to elevatedhydrogen pressure.

wherein M, R^(l3a) and A³ are each as defined above.

[Step LXVIII]

A compound represented by the formula (311) is treated with a strongbase such as n-butyllithium or lithium diisopropylamide in a dry solventsuch as tetrahydrofuran, diethyl ether or hexamethylphosphorous triamideat from −100 to 0° C. The anion thus obtained is then treated with ametal salt such as cupric iodide to thereby effect a metal exchangereaction. The copper complex thus obtained is treated with anappropriate acid halide to thereby give a compound represented by theformula (312).

[Step XIII]

An appropriately protected 4-piperidinecarbaldehyde is reacted with aHorner-Emmons reagent represented by the formula (312) in a solvent inthe presence of an appropriate base to thereby give a compoundrepresented by the formula (313). As the solvent, use can be made of drysolvents such as N,N-dimethylformamide, tetrahydrofuran or diethylether. As the base, use can be made of sodium hydride, potassiumtert-butoxide, n-butyllithium, lithium diisopropylamide, etc. Thereaction can be effected at from −100° C. to the reflux temperature ofthe solvent.

[Step XIV]

The compound represented by the formula (313) is subjected to areduction reaction with the use of an appropriate metal catalyst in asolvent to thereby give a compound represented by the formula (314). Thereaction may be carried out in, for example, a solvent such as methanol,ethanol, ethyl acetate or tetrahydrofuran with the use of palladium,platinum (IV) oxide, etc. as the catalyst under normal to elevatedhydrogen pressure.

wherein M, R^(l3a), R^(a) and A³ are each as defined above; and L²represents a substituent such as methylsulfonyl, nitryl, tetarzol-5-ylor 8-methyl-8-azabicyclo[3.2.1]octan-3-yl.

[Step XI]

A compound represented by the formula (147) is reacted with anappropriate base in an aqueous solvent followed by hydrolysis to therebygive a compound having a carboxyl group represented by the formula(315). As the solvent, use can be made of alcoholic solvents such asmethanol or ethanol or solvent mixtures such asalcohol/tetrahydrofuran/water. As the base, use can be made of sodiumhydroxide, potassium hydroxide, etc. The reaction can be effected atfrom room temperature to the reflux temperature of the solvent.

[Step LXXXX]

The carboxylic acid represented by the formula (315) is reacted with anappropriate diimide, an appropriate chloroformate, an appropriatedichlorophosphonate or carbonyldiimidazole at from 0 to 60° C. in anappropriate dry solvent such as N,N-dimethylformamide, tetrahydrofuran,acetonitrile or dichloromethane optionally in the presence of anappropriate base such as pyridine, triethylamine orN,N-diisopropylamine. The activated ester thus obtained is then reactedwith an appropriate amine or amine derivative to thereby give an amiderepresented by the formula (316).

wherein G, Z, E, X¹, l¹, R^(k), R^(l), R′ and Hal are each as definedabove.

[Step XXVIII]

An alcohol represented by the formula (131) is treated with acyanidation reagent such as sodium cyanide or potassium cyanide in anappropriate solvent such as dimethyl sulfoxide to thereby give a nitrilerepresented by the formula (317). The reaction can be effected at fromroom temperature to 100° C.

[Step XVII]

The cyano compound of the formula (317) is treated with a base such assodium hydroxide or potassium hydroxide in an alcoholic solvent such asethanol, propanol, ethylene glycol or diethylene glycol and heated underreflux to thereby give a carboxylic acid of the formula (318).

[Step LXXXXI]

The carboxylic acid of the formula (318) is treated with diphenylphosphate azide in an appropriate dry solvent such as tetrahydrofuran inthe presence of an appropriate tertiary amine base such astriethylamine. The intermediate thus obtained is then treated with anappropriate secondary or primary amine to thereby give a urea derivativerepresented by the formula (319).

wherein G, Z, E, X¹, l¹, A¹, R^(k), R^(l), R′ and Hal are each asdefined above.

[Step XXXXVII]

An amine represented by the formula (276) is reacted with chloroacetylchloride optionally in an appropriate solvent in the presence of anappropriate base such as pyridine, triethylamine orN,N-diisopropylethylamine to thereby give an amide represented by theformula (320). As the solvent, use can be made of dryN,N-dimethylformamide, dry dichloromethane, etc. The reaction can beeffected at from 0° C. to room temperature.

[Step LXXXIX]

The halogen compound represented by the formula (320) is treated with anappropriate amine optionally in an appropriate solvent such asdichloromethane or dry N,N-dimethylformamide in the presence of anappropriate base such as anhydrous potassium carbonate, pyridine,triethylamine or N,N-diisopropylethylamine to thereby give a compoundrepresented by the formula (321).

wherein G, Z, E, X¹, l¹, A¹, R^(k), R^(l), R′ and Hal are each asdefined above.

[Step LXXXX]

A carboxylic acid represented by the formula (318) is reacted with anappropriate diimide, an appropriate chloroformate, an appropriatedichlorophosphonate or carbonyldiimidazole at from 0 to 60° C. in anappropriate dry solvent such as N,N-dimethylformamide, tetrahydrofuran,acetonitrile or dichloromethane optionally in the presence of anappropriate base such as pyridine, triethylamine orN,N-diisopropylethylamine. The activated ester thus obtained is thenreacted with an appropriate amine or amine derivative to thereby give anamide represented by the formula (322).

wherein G, Z, E, X¹, l¹, A¹, R^(k), R^(l), R′ and Hal are each asdefined above.

[Step LXXXXII]

A ketone represented by the formula (323) is treated with a brominationagent such as tetra-n-butylammonium tribromide or N-bromosuccinimide ina solvent mixture such as methanol/dichloromethane or a solvent such astetrahydrofuran to thereby give a halogen compound represented by theformula (324).

[Step LXXXIX]

The halogen compound of the formula (324) is treated with an appropriateamine optionally in an appropriate solvent such as dichloromethane ordry N,N-dimethylformamide in the presence of an appropriate base such asanhydrous potassium carbonate, pyridine, triethylamine orN,N-diisopropylethylamine to thereby give a compound represented by theformula (325).

wherein G, Z, E, X¹, l¹ and A³ are each as defined above.

[Step LXXXXIII]

An α,β-unsaturated ketone compound represented by the formula (326) istreated with mercaptoacetic acid in an appropriate dry solvent such asdichloromethane or tetrahydrofuran in the presence of a strong base suchas sodium hydride to thereby give a compound represented by the formula(327). This reaction is effected preferably at from 0° C. to roomtemperature.

wherein G, Z, E, X², l² and R are each as defined above.

[Step LXXIX]

A compound represented by the formula (258) having a nucleophilicheteroatom is treated with a strong base such as sodium hydride orlithium diisopropylamide in a dry solvent such as tetrahydrofuran orN,N-dimethylformamide. The anion thus obtained is then treated with ahalogen compound (328) at from 0 to 100° C. or reacted in an alcoholicsolvent such as ethanol or methanol optionally in the presence of a basesuch as triethylamine at from room temperature to the refluxtemperature. Thus a compound represented by the formula (329) can beobtained.

[Step LXXXXIV]

When the compound represented by the formula (258) is a primary amine,it is treated with an aldehyde represented by the formula (330) in anappropriate solvent such as toluene or benzene at from room temperatureto the reflux temperature. The intermediate thus obtained is treatedwith an appropriate reducing agent such as sodium borohydride or sodiumborocyanohydride in an appropriate alcoholic solvent such as ethanol ormethanol or in an appropriate solvent mixture such asthanol/tetrahydrofuran to thereby give a compound represented by theformula (329).

[Step VIII]

The compounds represented by the formulae (329) and (333) are treatedwith an appropriate acid such as hydrochloric acid, trifluoroacetic acidor acetic acid optionally in an appropriate solvent such asdichloromethane or tetrahydrofuran to thereby give amines represented bythe formulae (331) and (332).

[Step XI]

When the compounds represented by the formulae (329) and (331) have anester group in the molecule, these compounds are reacted with anappropriate base in an aqueous solvent to thereby give compounds havinga carboxyl group represented by the formulae (333) and (332)respectively. As the solvent, use can be made of alcoholic solvents suchas methanol or ethanol or solvent mixtures such asalcohol/tetrahydrofuran/water. As the base, use can be made of sodiumhydroxide or potassium hydroxide. The reaction can be carried out atfrom room temperature to the reflux temperature of the solvent.

wherein G, Z, E, X², l², X_(n), Hal and R′ are each as defined above; D¹represents a heteroaryl ring such as pyridine or purine; l is 0 or 1;and R^(m) represents hydrogen, optionally substituted alkyl optionallyhaving a heteroatom and optionally having an optionally substitutedaryl, heteroaryl or heterocycloalkyl ring, optionally substituted aryl,optionally substituted heteroaryl or optionally substitutedheterocycloalkyl.

[Step LXXXXV]

A halide represented by the formula (335) is reacted with an alkyne in adry solvent such as N,N-dimethylformamide at from room temperature to120° C. in the presence of a catalyst such asdichlorobis(triphenylphosphine)palladium with triphenylphosphine, anoxidizing agent such as cupric iodide and a base such as triethylamineto thereby give compounds represented by the formulae (336) and (338).

[Step XIV]

The compounds represented by the formulae (336) and (339) are subjectedto a reduction reaction with the use of an appropriate metal catalyst ina solvent to thereby give compounds represented by the formulae (337)and (342). The reaction may be carried out in, for example, a solventsuch as methanol, ethanol, ethyl acetate or tetrahydrofuran with the useof palladium, platinum (IV) oxide, etc. as the catalyst under normal toelevated hydrogen pressure.

[Step LI]

The compound represented by the formula (338) is treated with a reagentsuch as tetra-n-butylammonium fluoride or caesium fluoride in a drysolvent such as tetrahydrofuran to thereby give a carboxylic acidrepresented by the formula (339). The reaction is effected preferably atfrom 0° C. to room temperature.

[Step LXXXXVI]

The alkyne represented by the formula (339) is reacted withdimethylcarbamoyl chloride optionally in a dry solvent such asN,N-dimethylformamide at from room temperature to 120° C. in thepresence of a catalyst such as dichlorobis(triphenylphosphine)palladiumwith triphenylphosphine, an oxidizing agent such as cupric iodide and abase such as triethylamine to thereby give an amide represented by theformula (340).

[Step LXXXXVII]

The alkyne represented by the formula (339) is reacted with a strongbase such as n-butyllithium in a dry solvent such as tetrahydrofuran atfrom −100 to 0° C. and the anion thus obtained is treated with dry iceto thereby give a compound represented by the formula (341).

wherein L¹ and R^(d) are each as defined above; and A⁹ representsheteroaryl having an acidic proton group such as NH (for example,imidazole or purine).

[Step LXXXXVIII]

The compound represented by the formula (344) is reacted withN,N′-disuccinimidyl carbonate, carbonyldiimidazole, etc. in a drysolvent such as acetonitrile or N,N-dimethylformamide at from 0° C. tothe reflux temperature to thereby give a compound represented by theformula (345).

[Step LIL]

The compound represented by the formula (344) is reacted with an acidanhydride such as trifluoroacetic anhydride at from 50 to 150° C. underelevated pressure to thereby give a purine derivative represented by theformula (346).

wherein A⁹, Hal, R^(d) and R^(e) are each as defined above; and R^(pb)represents an alcohol protective group having a silyl group.

[Step C]

A halide represented by the formula (347) is reacted with an appropriatevinyl-tri-n-butyltin (IV) derivative in a dry solvent such asN,N-dimethylformamide at from room temperature to 120° C. in thepresence of a catalyst such as dichlorobis(triphenylphosphine)palladiumand triphenylphosphine to thereby give an alkene represented by theformula (348).

[Step VIII]

The compound represented by the formula (348) is treated with anappropriate acid such as hydrochloric acid, trifluoroacetic acid oracetic acid optionally in an appropriate solvent such as dichloromethaneor tetrahydrofuran to thereby give a ketone represented by the formula(349).

[Step XXIV]

The compound represented by the formula (349) is treated with a reducingagent such as sodium borohydride in a solvent to thereby give a compoundrepresented by the formula (350). As the solvent, use can be made ofmethanol, ethanol, etc. The reaction can be effected at from 0° C. tothe reflux temperature.

[Step LXXXVIII]

The alcohol represented by the formula (350) is reacted with asilylation agent such as chloro-tert-butyldimethylsilane,(tert-butyldimethylsilyl)trifluoroacetate orN-methyl-N-(tert-butyldimethylsilyl)trifluoroacetamide in an appropriatesolvent optionally in the presence of a base such as imidazole, pyridineor N,N-diisopropylethylamine to thereby give an ester compoundrepresented by the formula (351). As the solvent, use can be made of adry solvent such as N,N-dimethylformamide, acetonitrile ordichloromethane. The reaction can be effected at from 0 to 40° C.

wherein G, Z, E, X², l², Q, Hal, R^(k), R^(l) and R′ are each as definedabove.

[Step LXXIX]

An appropriate purine derivative is treated with a strong base such assodium hydride or lithium diisopropylamide in a dry solvent such astetrahydrofuran or N,N-dimethylformamide. The anion thus obtained isthen treated with a halogen compound (352) at from 0 to 100° C. tothereby give compounds represented by the formulae (353) and (354).

[Step LXXXIX]

The halides represented by the formulae (353) and (354) are treated withan appropriate amine optionally in an appropriate solvent such asdichloromethane or methanol at from room temperature to the refluxtemperature to thereby give compounds represented by the formulae (355)and (356) respectively.

wherein G, Z, E, X², l², Q, Hal, M, R^(a) and R′ are each as definedabove.

[Step LXXIX]

A purine derivative represented by the formula (357) is treated with astrong base such as sodium hydride or lithium diisopropylamide in a drysolvent such as tetrahydrofuran or N,N-dimethylformamide. The anion thusobtained is then treated with a halogen compound (352) at from 0 to 100°C. to thereby give compounds represented by the formulae (358) and(359).

[Step CI]

The compounds represented by the formulae (358) and (359) are treatedwith boron tribromide in an appropriate dry solvent such asdichloromethane at from 0° C. to the reflux temperature to thereby givecompounds represented by the formulae (360) and (361).

wherein G, Z, E, X², l², Q, Hal, R^(k) and R′ are each as defined above.

[Step C]

A halide represented by the formula (354) is reacted with an appropriatevinyl-tri-n-butyltin (IV) derivative in a dry solvent such asN,N-dimethylformamide at from room temperature to 120° C. in thepresence of a catalyst such as dichlorobis(triphenylphosphine)palladiumand triphenylphosphine to thereby give an alkene represented by theformula (362).

[Step XIV]

The compound represented by the formula (362) is subjected to areduction reaction with the use of an appropriate metal catalyst in asolvent to thereby give a compound represented by the formula (363). Thereaction may be carried out in, for example, a solvent such as methanol,ethanol, ethyl acetate or tetra-

wherein G, Z, E, X², l², Q, Hal, R^(d), R^(e) and R′ are each as definedabove.

[Step C]

Halides represented by the formulae (353) and (354) are reacted with anappropriate vinyl-tri-n-butyltin (IV) derivative in a dry solvent suchas N,N-dimethylformamide at from room temperature to 120° C. in thepresence of a catalyst such as dichlorobis(triphenylphosphine)palladiumand triphenylphosphine to thereby give alkenes represented by theformulae (364) and (366) respectively.

[Step VIII]

The compounds represented by the formulae (364) and (366) are treatedwith an appropriate acid such as hydrochloric acid, trifluoroacetic acidor acetic acid optionally in an appropriate solvent such asdichloromethane or tetrahydrofuran to thereby give ketones representedby the formulae (365) and (367) respectively.

[Step VII]

The amine represented by the formula (367) is treated with a base suchas sodium hydride and a protecting reagent such as methoxymethylchloride in a solvent to thereby give a compound represented by theformula (368).

[Step XXIV]

The compound represented by the formula (368) is treated with a reducingagent such as sodium borohydride in a solvent to thereby give a compoundrepresented by the formula (369). As the solvent, use can be made ofmethanol, ethanol, etc. The reaction can be effected at from 0° C. tothe reflux temperature.

[Step XXXXI]

A compound represented by the formula (368) is treated withmethyllithium or a methylmagnesium halide in a solvent such as drytetrahydrofuran, diethyl ether or dimethoxyethane at from −78° C. to theboiling point of the solvent to thereby give an alcohol represented bythe formula (370).

drofuran with the use of palladium, platinum (IV) oxide, etc. as thecatalyst under normal to elevated hydrogen pressure.

wherein G, Z, E, X², l², Q, Hal, R^(pb), R^(e) and R′ are each asdefined above.

[Step LXXIX]

A purine derivative represented by the formula (351) is treated with astrong base such as sodium hydride or lithium diisopropylamide in a drysolvent such as tetrahydrofuran or N,N-dimethylformamide. The anion thusobtained is then treated with a halogen compound (352) at from 0 to 100°C. to thereby give a compound represented by the formula (371).

[Step VIII]

The compound represented by the formula (371) is treated with anappropriate acid such as hydrochloric acid, trifluoroacetic acid oracetic acid optionally in an appropriate solvent such as dichloromethaneor tetrahydrofuran to thereby give a compound represented by the formula(372). Trifluoroacetic acid is the most desirable acid. The reaction iseffected preferably at from 0° C. to room temperature.

[Step LI]

The compound represented by the formula (372) is treated with a reagentsuch as tetra-n-butylammonium fluoride or caesium fluoride in a drysolvent such as tetrahydrofuran to thereby give an alcohol representedby the formula (373). The reaction is effected preferably at from 0° C.to room temperature.

wherein G, Z, E, X², l², Q, Hal, R^(k), R^(l) and R′ are each as definedabove.

[Step LXXXIX]

A halide represented by the formula (374) is treated with an appropriateamine in an appropriate solvent such as methanol, ethanol ortetrahydrofuran or a mixture thereof at from 50 to 150° C. underelevated pressure to thereby give a compound represented by the formula(375).

wherein G, Z, E, X², l², X_(n), Q, R^(d), R^(e), R^(k), R^(m) and R areeach as defined above; V² represents cyano, methylsulfonyl or 2-pyridyl;when X_(n) ¹ is an alkylene side chain having n carbon atoms and n is 0,then the substituent is bonded directly to D^(d) or X_(n); D² representsa heteroaryl ring such as imidazole, purine, or 4-phenylimidazole; and lis 0 or 1.

[Step CII]

An amine represented by the formula (376) is treated withN,N-dimethylformamide dimethyl acetal in a solvent mixture oftetrahydrofuran with methanol at from room temperature to the refluxtemperature to thereby give an amidine represented by the formula (377).

[Step XXXXIX]

The amine represented by the formula (376) is reacted with anappropriate imidate or thioimidate in a solvent such as acetonitrile ormethanol to thereby give a compound represented by the formula (378). Itis preferable that the reaction is carried out at from 0 to 40° C.

wherein G, Z, E, X², l², Q, R^(k), R^(l), R^(m), Nu, X_(n), X_(n) ¹, D²,l and R are each as defined above.

[Step CIII]

A nitrile derivative represented by the formula (379) is reacted withammonium chloride, an appropriate primary amine hydrochloride or anappropriate secondary amine hydrochloride in a dry solvent such astoluene or benzene at from 50° C. to the reflux temperature in thepresence of trimethylaluminum to thereby give an amidine represented bythe formula (380).

[Step XXIV]

The compound represented by the formula (379) is treated with a reducingagent such as aluminum lithium hydride or lithium borohydride in asolvent such as dry tetrahydrofuran or dry diethyl ether to thereby givean amine of the formula (381). The reaction can be effected at from 0°0C. to the reflux temperature.

[Step LXXXV]

The nitrile compound represented by the formula (379) is treated with anappropriate acid in an alcoholic solvent to thereby give an imidaterepresented by the formula (382) (i.e., the so-called Pinner reaction).It is preferable to use hydrochloric acid as the acid. The reaction ispreferably effected in methanol/dichloromethane at from −20 to 0° C.

[Step CIV]

The imidate represented by the formula (382) is reacted with cyanamidein an appropriate solvent in the presence of sodiummonohydrogenphosphate and sodium dihydrogenphosphate to thereby give aderivative represented by the formula (383). As the solvent, it ispreferable to use acetonitrile. The reaction is effected preferably atfrom 0° C. to room temperature.

[Step LXXXVI]

The imidate represented by the formula (383) is reacted with an amine oran amide in an appropriate solvent to thereby give compounds representedby the formulae (384) and (385). As the solvent, use can be made ofacetonitrile, tetrahydrofuran, etc. The reaction is effected preferablyat from 0° C. to reflux temperature.

wherein G, Z, E, X^(2′), l², Q, R^(k), R^(l), R^(m), Nu, X_(n), X_(n) ¹,D², l and R are each as defined above; V³ represents nitryl, methyl,sulfonyl, phenylsulfonyl, trifluoromethylsulfonyl, sulfamoyl orN,N-dimethylcarbamoyl; and A⁵ represents optionally substitutedtetrahydropyrimidine.

[Step CV]

A nitrile represented by the formula (379) is reacted with sodiumhydrosulfide and hydrogen sulfide in an appropriate alcoholic solventsuch as methanol at from −30 to 100° C. under elevated pressure tothereby give a thioamide represented by the formula (386).

[Step CVI]

The thioamide represented by the formula (386) is reacted with analkylating agent such as methyl iodide in an appropriate solvent such asacetone. The thioimide thus obtained is then reacted with an appropriateamine or a derivative of amide or sulfonamide in an appropriatealcoholic solvent at from room temperature to 60° C. to thereby givederivatives represented by the formulae (387), (388), (389) and (390).

wherein G, Z, E, X², l², Q and R′ are each as defined above.

[Step VIII]

A compound represented by the formula (334) is treated with anappropriate acid such as hydrochloric acid, trifluoroacetic acid oracetic acid optionally in an appropriate solvent such as dichloromethaneor tetrahydrofuran to thereby give an amine represented by the formula(88a).

wherein G, Z, E, X², l², Q, R^(d), R^(m) and R′ are each as definedabove; and Ar represents aryl having no acidic proton or heteroarylhaving no acidic proton.

[Step XXXXI]

A compound represented by the formula (108) is treated withmethyllithium or a methylmagnesium halide in a solvent such as drytetrahydrofuran, diethyl ether or dimethoxyethane at from −78° C. to theboiling point of the solvent to thereby give an alcohol represented bythe formula (391).

[Step LXI]

The compound represented by the formula (108) is reacted in anappropriate solvent with an aryl-Grignard or aryllithium obtained by ahalogen-metal exchange reaction or a hydrogen-metal exchange reaction oran aryl cerium complex obtained by treating the former compound withcerium (III) chloride to thereby give a compound represented by theformula (392). As the solvent, use can be made of a dry solvent such astetrahydrofuran, diethyl ether or dimethoxyethane. The reaction can beeffected at from −100° C. to the reflux temperature of the solvent.

[Step LIII]

A ketone represented by the formula (108) is reacted with an anionobtained by treating an alkyne with a strong base such as n-butyllithiumor lithium diisopropylamine in a dry solvent such as tetrahydrofuran ordiethyl ether to thereby give a compound represented by the formula(393). The reaction can be effected at from −100° C. to roomtemperature.

[Step XIV]

The compound represented by the formula (393) is subjected to areduction reaction in a solvent with the use of an appropriate metalcatalyst to thereby give a compound represented by the formula (394).For example, use can be made of a hydrogenation reaction effected in asolvent such as methanol, ethanol, ethyl acetate or tetrahydrofuran withthe use of palladium, platinum (IV) oxide, etc. under normal to elevatedhydrogen pressure.

wherein G, Z, E, X², l², Q, Ar, R^(e) and R′ are each as defined above.

[Step CVII]

Compounds represented by the formulae (392) and (397) are reacted withdimethylaminosulfur trifluoride optionally in a dry solvent such asdichloromethane at from room temperature to 50° C. to thereby givecompounds represented by the formulae (395) and (401) respectively.

[Step XXI]

The compound represented by the formula (392) is treated with a basesuch as sodium hydride or sodium methoxide in a solvent such asdimethoxyethane, tetrahydrofuran or N,N-dimethylformamide and thenreacted with an alkyl halide to thereby give a derivative represented bythe formula (396). This reaction is effected preferably at from 100° C.to room temperature.

[Step XXIX]

A solution of the alcohol represented by the formula (392) in, forexample, methylene chloride is added to a reaction mixture obtained fromoxalyl chloride and dimethyl sulfoxide and treated with a base such astriethylamine. Alternatively, it is treated with pyridinium dichromatein a solvent such as dichloromethane or treated with manganese dioxidein a solvent such as dichloromethane. Thus, a ketone represented by theformula (397) can be obtained.

[Step XXXXI]

The compound represented by the formula (397) is treated withmethyllithium or a methylmagnesium halide in a solvent such as drytetrahydrofuran, diethyl ether or dimethoxyethane at from −78° C. to theboiling point of the solvent to thereby give an alcohol represented bythe formula (398).

[Step CVIII]

The compound represented by the formula (398) is reacted withchloromethanesulfonyl chloride in an appropriate dry solvent such asdichloromethane in the presence of an appropriate base such as pyridineto thereby give a compound represented by the formula (399). Thereaction can be effected at from 0° C. to the reflux temperature.

[Step XIV]

The compound represented by the formula (399) is subjected to areduction reaction in a solvent with the use of an appropriate metalcatalyst to thereby give a compound represented by the formula (400).For example, use can be made of a hydrogenation reaction effected in asolvent such as methanol, ethanol, ethyl acetate or tetrahydrofuran withthe use of palladium, platinum (IV) oxide, etc. under normal to elevatedhydrogen pressure.

wherein G, Z, E, X², l², Q, A⁸, R^(pb) and R′ are each as defined above.

[Step LXXXXIII]

A compound represented by the formula (482) is treated withmercaptoacetic acid in an appropriate dry solvent such asdichloromethane or tetrahydrofuran in the presence of a strong base suchas sodium hydride to thereby give a compound represented by the formula(402). The reaction can be effected at from 0 to 100° C.

[Step XI]

The compound represented by the formula (402) is reacted with anappropriate base in an aqueous solvent to thereby give a compound havinga carboxyl group (403). As the solvent, use can be made of alcoholicsolvents such as methanol or ethanol or solvent mixtures such asalcohol/tetrahydrofuran/water. As the base, use can be made of sodiumhydroxide, potassium hydroxide, etc. The reaction can be effected atfrom room temperature to the reflux temperature of the solvent.

[Step LXXXVIII]

The alcohol represented by the formula (482) is reacted with asilylation agent such as chloro-tert-butyldimethylsilane,(tert-butyldimethylsilyl)trifluoroacetate orN-methyl-N-(tert-butyldimethyl-silyl)trifluoroacetamide in anappropriate solvent optionally in the presence of a base such asimidazole, pyridine or N,N-diisopropylethylamine to thereby give anester compound represented by the formula (404). As the solvent, use canbe made of a dry solvent such as N,N-dimethylformamide, acetonitrile ordichloromethane. The reaction can be effected at from 0 to 40° C.

[Step LXXXXV]

A halide represented by the formula (404) is reacted with an appropriatealkyne in a dry solvent such as N,N-dimethylformamide at from roomtemperature to 120° C. in the presence of a catalyst such as palladium(II) acetate with triphenylphosphine and a base such as triethylamine tothereby give a compound represented by the formula (405).

[Step XIV]

The compound represented by the formula (405) is subjected to areduction reaction with the use of an appropriate metal catalyst in asolvent to thereby give compound represented by the formula (406). Thereaction may be carried out in, for example, a solvent such as methanol,ethanol, ethyl acetate or tetrahydrofuran with the use of palladium,platinum (IV) oxide, etc. as the catalyst under normal to elevatedhydrogen pressure.

[Step LI]

The compounds represented by the formulae (405) and (406) are treatedwith a reagent such as tetra-n-butylammonium fluoride or caesiumfluoride in a dry solvent such as tetrahydrofuran to thereby givecompounds represented by the formulae (408) and (407) respectively. Thereaction is effected preferably at from 0° C. to room temperature.

wherein G, Z, E, X², l², Q, A⁸ and R′ are each as defined above; andA^(1a) represents saturated heterocycloalkyl.

[Step XXXXVI]

An alcohol represented by the formula (409) is reacted with a carboxylicanhydride and an acid halide optionally in an appropriate solvent in thepresence of an appropriate base such as pyridine, triethylamine orN,N-diisopropylethylamine to thereby give an ester represented by theformula (410). As the solvent, use can be made of dry dichloromethane,etc. The reaction can be effected at from 0° C. to reflux temperature.

[Step XIV]

The compound represented by the formula (410) is subjected to areduction reaction with the use of an appropriate metal catalyst in asolvent to thereby give a compound represented by the formula (411). Thereaction may be carried out in, for example, a solvent such as methanol,ethanol, ethyl acetate or tetrahydrofuran with the use of palladium,platinum (IV) oxide, etc. as the catalyst under normal to elevatedhydrogen pressure.

[Step CIX]

The compound represented by the formula (410) is subjected to areduction reaction with the use of an appropriate metal catalyst in asolvent to thereby give a compound represented by the formula (412). Thereaction may be carried out in, for example, a solvent such as methanol,ethanol, ethyl acetate or tetrahydrofuran with the use of palladium,platinum (IV) oxide, etc. as the catalyst under normal to elevatedhydrogen pressure.

wherein G, Z, E, X², l², Q, A⁹ and R′ are each as defined above; and RPCrepresents a protective group such as trityl or dimethylsulfamoyl.

[Step LXI]

A compound represented by the formula (108) is reacted in an appropriatesolvent with an aryl-Grignard or aryllithium obtained from the compoundrepresented by the formula (413) by a halogen-metal exchange reaction ora hydrogen-metal exchange reaction or an arylcerium complex obtained bytreating the former compound with cerium (III) chloride to thereby givea compound represented by the formula (414). As the solvent, use can bemade of a dry solvent such as tetrahydrofuran, diethyl ether ordimethoxyethane. The reaction can be effected at from −100° C. to thereflux temperature of the solvent.

[Step VIII]

When R^(pc) is a protective group which can be eliminated by treatingwith an acid, such as trityl, a compound represented by the formula(414) is treated with an appropriate acid such as hydrochloric acid,trifluoroacetic acid or acetic acid optionally in an appropriate solventsuch as dichloromethane or tetrahydrofuran to thereby give an aminerepresented by the formula (415).

[Step XXXXVI]

An alcohol represented by the formula (414) is reacted with phenylchlorothioformate optionally in an appropriate solvent in the presenceof an appropriate base such as pyridine, triethylamine orN,N-diisopropylethylamine to thereby give an ester represented by theformula (416). As the solvent, use can be made of dry acetonitrile, drydichloromethane, etc. The reaction can be effected at from 0° C. toreflux temperature.

[Step CX]

The compound represented by the formula (416) is treated with a reducingagent such as tri-n-butyltin (IV) hydride in an appropriate solvent suchas toluene or benzene at from room temperature to the reflux temperatureto thereby give a compound represented by the formula (417).

[Step XI]

When R^(pc) is a protective group which can be eliminated by treatingwith an alkali, such as dimethylsulfamoyl, the compounds represented bythe formulae (414) and (417) are reacted with an appropriate base in anaqueous solvent to thereby give compounds represented by formulae (415)and (418) respectively. As the solvent, use can be made of alcoholicsolvents such as methanol or ethanol or solvent mixtures such asalcohol/tetrahydrofuran/water. As the base, use can be made of sodiumhydroxide, potassium hydroxide, etc. The reaction can be effected atfrom room temperature to the reflux temperature of the solvent.

wherein G, Z, E, X², l², Q, A⁸ and R′ are each as defined above.

[Step LXI]

A compound represented by the formula (108) is reacted in an appropriatesolvent with a lithium anion obtained from the compound represented bythe formula (419) by a hydrogen-metal exchange reaction to thereby givea compound represented by the formula (420). As the solvent, use can bemade of a dry solvent such as tetrahydrofuran, diethyl ether ordimethoxyethane. The reaction can be effected at from −100° C. to thereflux temperature of the solvent.

wherein G, Z, E, X², l², Q, R^(a), A⁸ and R′ are each as defined above.

[Step LXI]

A compound represented by the formula (105) is reacted in an appropriatesolvent with a lithium anion obtained from the compound represented bythe formula (419) by a hydrogen-metal exchange reaction to thereby givea compound represented by the formula (421). As the solvent, use can bemade of a dry solvent such as tetrahydrofuran, diethyl ether ordimethoxyethane. The reaction can be effected at from −100° C. to thereflux temperature of the solvent.

wherein G, Z, E, X², l², Q, Ar and R′ are each as defined above.

[Step XXXII]

An appropriate arylmethyltriphenylphosphonium bromide orheteroarylmethyltriphenylphosphonium bromide is treated with anappropriate base such as potassium tert-butoxide or butyllithium in asolvent such as toluene, xylene or tetrahydrofuran followed by areaction with an aldehyde represented by the formula (108). Thus acompound represented by the formula (422) can be obtained. The reactiontemperature preferably ranges from −78° C. to the reflux temperature ofthe solvent.

[Step XIV]

The compound represented by the formula (422) is subjected to areduction reaction with the use of an appropriate metal catalyst in asolvent to thereby give a compound represented by the formula (423). Thereaction may be carried out in, for example, a solvent such as methanol,ethanol, ethyl acetate or tetrahydrofuran with the use of palladium,platinum (IV) oxide, etc. as the catalyst under normal to elevatedhydrogen pressure.

wherein G, Z, E, X², l², Q, X_(n), X_(n) ¹, D², l and R′ are each asdefined above.

[Step XIV]

A compound represented by the formula (424) is subjected to a reductionreaction with the use of an appropriate metal catalyst in a solvent tothereby give a compound represented by the formula (376). The reactionmay be carried out in, for example, a solvent such as methanol, ethanol,ethyl acetate or tetrahydrofuran with the use of palladium, platinum(IV) oxide, etc. as the catalyst under normal to elevated hydrogenpressure.

wherein G, Z, E, X², l², L¹, Q, X_(n), X_(n) ¹, D², l and R′ are each asdefined above.

[Step XXXXVI]

An amine represented by the formula (376) is reacted with a carboxylicanhydride and an acid halide optionally in an appropriate solvent in thepresence of an appropriate base such as pyridine, triethylamine orN,N-diisopropylethylamine to thereby give amides represented by theformulae (426) and (429). As the solvent, use can be made of drydichloromethane, etc. The reaction can be effected at from 0° C. toreflux temperature.

[Step XXXXVII]

The compound represented by the formula (376) is reacted with anappropriate sulfonic anhydride or acid halide optionally in anappropriate solvent such as dichloromethane in the presence of anappropriate base such as pyridine, triethylamine orN,N-diisopropylethylamine to thereby give a compound represented by theformula (425).

[Step XXXXVIII]

The amine represented by the formula (376) is treated with an acidhalide of an appropriate sulfamic acid optionally in an appropriatesolvent such as dichloromethane in the presence of an appropriate basesuch as pyridine, triethylamine or N,N-diisopropylethylamine.Alternatively, it is treated with chlorosulfonyl isocyanate in a drysolvent such as tetrahydrofuran and the intermediate is treated with anappropriate acid such as formic acid. Alternatively, it is reacted withsulfamide in dimethoxyethane at 100° C. Thus, a compound represented bythe formula (428) can be obtained.

[Step LXXXIII]

The isoxazole represented by the formula (426) is treated withN,N-dimethylformamide dimethyl acetal in a dry solvent such astetrahydrofuran at from room temperature to the reflux temperature tothereby give a compound represented by the formula (427).

wherein G, Z, E, X², l², M, Q, R^(a), R^(c), R^(d), R^(k) and R′ areeach as defined above; and D³ represents an imidazole or pyridine ring.

[Step LXXXX]

A carboxylic acid represented by the formula (431) is reacted with anappropriate diimide, an appropriate chloroformate, an appropriatedichlorophosphonate or carbonyldiimidazole at from 0 to 60° C. in anappropriate dry solvent such as N,N-dimethylformamide, tetrahydrofuran,acetonitrile or dichloromethane optionally in the presence of anappropriate base such as pyridine, triethylamine orN,N-diisopropylethylamine. The activated ester thus obtained is thenreacted with ammonia to thereby give an amide represented by the formula(432).

[Step XI]

The compound represented by the formula (430) is reacted with anappropriate base in an aqueous solvent to thereby give a compound havinga carboxyl group (431). As the solvent, use can be made of alcoholicsolvents such as methanol or ethanol or solvent mixtures such asalcohol/tetrahydrofuran/water. As the base, use can be made of sodiumhydroxide, potassium hydroxide, etc. The reaction can be effected atfrom room temperature to the reflux temperature of the solvent.

[Step LXXXIX]

The ester represented by the formula (430) is treated with anappropriate amine optionally in an appropriate solvent such as methanol,ethanol or tetrahydrofuran at from room temperature to 150° C. underatmospheric or elevated pressure to thereby give a compound representedby the formula (432).

[Step XXXXI]

The compounds represented by the formulae (430) and (435) are treatedwith methyllithium or a methylmagnesium halide in a solvent such as drytetrahydrofuran, diethyl ether or dimethoxyethane at from −78° C. to theboiling point of the solvent to thereby give alcohols represented by theformulae (433) and (436) respectively.

[Step XXIV]

The compound represented by the formula (430) is treated with a reducingagent such as aluminum lithium hydride or lithium borohydride in asolvent such as dry tetrahydrofuran or dry diethyl ether to thereby givean amine of the formula (434). The reaction can be effected at from 0°C. to the reflux temperature.

[Step XXIX]

A solution of the alcohol represented by the formula (434) in, forexample, methylene chloride is added to a reaction mixture obtained fromoxalyl chloride and dimethyl sulfoxide and treated with a base such astriethylamine. Alternatively, it is treated with pyridinium dichromatein a solvent such as dichloromethane or treated with manganese dioxidein a solvent such as dichloromethane or N,N-dimethylformamide. Thus, acarbonyl compound represented by the formula (435) can be obtained.

[Step XIII]

The compound represented by the formula (435) is reacted with anappropriate Horner-Emmons reagent in a solvent in the presence of anappropriate base to thereby give a compound represented by the formula(437). As the solvent, use can be made of dry solvents such asN,N-dimethylformamide, tetrahydrofuran or diethyl ether. As the base,use can be made of sodium hydride, potassium tert-butoxide,n-butyllithium, lithium diisopropylamide, etc. The reaction can beeffected at from −100° C. to the reflux temperature of the solvent.

wherein G, Z, E, X², l², R′, Q and R^(m) are each as defined above.

[Step XXIV]

A compound represented by the formula (438) is treated with a reducingagent such as aluminum lithium hydride or lithium borohydride in asolvent such as dry tetrahydrofuran or dry diethyl ether, or with areducing agent such as sodium borohydride in an alcoholic solvent suchas methanol or ethanol to thereby give an amine of the formula (439).The reaction can be effected at from 0° C. to the reflux temperature.

wherein R^(a), A⁹ and R^(pc) are each as defined above.

[Step LXI]

An appropriate aldehyde is reacted in an appropriate solvent with anaryl-Grignard obtained from the compound represented by the formula(440) by a halogen-metal exchange reaction or a hydrogen-metal exchangereaction or an arylcerium complex obtained by treating the formercompound with cerium (III) chloride to thereby give compoundsrepresented by the formulae (441) and (446). As the solvent, use can bemade of a dry solvent such as tetrahydrofuran, diethyl ether ordimethoxyethane. The reaction can be effected at from −100° C. to thereflux temperature of the solvent.

[Step XXXXVI]

Alcohols represented by the formulae (441) and (447) are reacted with acarboxylic anhydride, a carboxylic phosphoric anhydride and an acidhalide optionally in an appropriate solvent in the presence of anappropriate base such as pyridine, triethylamine orN,N-diisopropylethylamine to thereby give esters represented by theformulae (442) and (448) respectively. As the solvent, use can be madeof dry dichloromethane, etc. The reaction can be effected at from 0° C.to reflux temperature.

[Step XIV]

The compounds represented by the formulae (442) and (448) are subjectedto a reduction reaction with the use of an appropriate metal catalyst ina solvent to thereby give compounds represented by the formulae (443)and (449) respectively. The reaction may be carried out in, for example,a solvent such as methanol, ethanol, ethyl acetate or tetrahydrofuranwith the use of palladium, platinum (IV) oxide, etc. as the catalystunder normal to elevated hydrogen pressure.

[Step XI]

The compounds represented by the formulae (441) and (443) are reactedwith an appropriate base in an aqueous solvent to thereby give compoundsrepresented by the formulae (445) and (444). As the solvent, use can bemade of alcoholic solvents such as methanol or ethanol or solventmixtures such as alcohol/tetrahydrofuran/water. As the base, use can bemade of sodium hydroxide, potassium hydroxide, etc. The reaction can beeffected at from room temperature to the reflux temperature of thesolvent.

[Step CXI]

The compound represented by the formula (446) is reacted with anappropriate base such as potassium hydroxide in an appropriate solventsuch as ethanol at from room temperature to the reflux temperature. Theintermediate thus obtained is then treated with an acid such as sulfuricacid in an appropriate solvent such as methanol or ethanol at from roomtemperature to the reflux temperature to thereby give compoundsrepresented by the formulae (447) and (450).

wherein G, Z, E, X², l², R′, Q, X_(n), X_(n) ¹, D² and l are each asdefined above.

[Step CXII]

An aldehyde represented by the formula (451) is treated with3-hydroxy-3-methyl-2-butanone in a solvent such as methanol ortetrahydrofuran or a mixture thereof in the presence of an appropriatebase such as lithium hydroxide to thereby give a compound represented bythe formula (452).

[Step XIV]

The compound represented by the formula (452) is subjected to areduction reaction with the use of an appropriate metal catalyst in asolvent to thereby give a compound represented by the formula (453). Thereaction may be carried out in, for example, a solvent such as methanol,ethanol, ethyl acetate or tetrahydrofuran with the use of palladium,platinum (IV) oxide, etc. as the catalyst under normal to elevatedhydrogen pressure.

wherein R^(n) represents methyl or tert-butyloxy.

[Step XXXXVI]

An amine represented by the formula (454) is reacted with sodium hydrideoptionally in an appropriate solvent in the presence of an appropriatebase such as pyridine, triethylamine or N,N-diisopropylethylamine andthe free compound thus obtained is then reacted with a carboxylicanhydride and an acid halide to thereby give an amide represented by theformula (455). As the solvent, it is preferable to use dryN,N-dimethylformamide. The reaction can be effected at from 0° C. to thereflux temperature.

[Step VII]

The amine represented by the formula (455) is treated with a base suchas sodium hydride and a protecting reagent such as(2-trimethylsilyl)ethoxymethyl chloride in a solvent such as dryN,N-dimethylformamide at from 0° C. to room temperature to thereby givea compound represented by the formula (456).

wherein G, Z, E, X², l² and R′ are each as defined above.

[Step VIII]

A compound represented by the formula (457) is treated with anappropriate acid such as hydrochloric acid, trifluoroacetic acid oracetic acid optionally in an appropriate solvent such as dichloromethaneor tetrahydrofuran to thereby give an amine represented by the formula(458).

wherein Hal, R^(d) and R^(m) are each as defined above.

[Step XV]

A compound represented by the formula (459) is reacted with a base suchas sodium hydride in a solvent such as dry N,N-dimethylformamide. Thenthe anion thus obtained is reacted with an appropriate halide at fromroom temperature to 100° C. to thereby give a compound represented bythe formula (460).

[Step LXXXXIII]

The diester represented by the formula (460) is treated with a base suchas sodium hydride in a solvent such as dry N,N-dimethylformamide at from0° C. to room temperature. Then the anion thus obtained is reacted witha halide represented by the formula (461) at from room temperature to100° C. to thereby give a compound represented by the formula (462).

[Step XI]

The compound represented by the formula (462) is reacted with anappropriate base such as sodium hydroxide or potassium hydroxide in analcoholic solvent such as methanol or ethanol or an aqueous solvent suchas a solvent mixture of alcohol, tetrahydrofuran and water at from roomtemperature to the reflux temperature the solvent. Alternatively, it isreacted with lithium chloride in a solvent such as dryN,N-dimethylformamide. Thus compounds represented by the formulae (463)and (465) can be obtained.

[Step XIV]

The compounds represented by the formulae (463) and (465) are subjectedto a reduction reaction with the use of an appropriate metal catalyst ina solvent to thereby give compounds represented by the formulae (464)and (466). The reaction may be carried out in, for example, a solventsuch as methanol, ethanol, ethyl acetate or tetrahydrofuran with the useof palladium, platinum (IV) oxide, etc. as the catalyst under normal toelevated hydrogen pressure.

wherein G, Z, E, X², l², Nu, M, R′ and R^(a) are each as defined above.

[Step LXXXXIV]

A compound represented by the formula (460) is reacted with an aldehyderepresented by the formula (108) in an appropriate solvent such astoluene or benzene at from room temperature to the reflux temperature.The intermediate thus obtained is then treated with an appropriatereducing agent such as sodium borohydride or sodium borocyanohydride inan appropriate alcoholic solvent such as ethanol or methanol or anappropriate solvent mixture such as ethanol/tetrahydrofuran at from 50°C. to the reflux temperature to thereby give a compound represented bythe formula (468).

wherein G, Z, Q, E, X², l², R′, L¹, R^(k) and R^(m) are each as definedabove; and R^(ml) has the same meaning as that of R^(m), provided thatwhen R^(m) and R^(ml) both exist in the molecule, then they may be thesame or different.

[Step XXI]

An amine represented by the formula (469) is reacted with an appropriatealkyl halide in the presence of an appropriate amine such as pyridine,triethylamine or N,N-diisopropylethylamine in a solvent such asdichloromethane, tetrahydrofuran or N,N-dimethylformamide to therebygive an amine represented by the formula (470).

[Step XXXXVI]

An amine represented by the formula (469) is reacted with a carboxylicanhydride and an acid halide optionally in an appropriate solvent in thepresence of an appropriate base such as pyridine, triethylamine orN,N-diisopropylethylamine to thereby give an amide represented by theformula (475). As the solvent, use can be made of dry dichloromethane,etc. The reaction can be effected at from 0° C. to reflux temperature.

[Step LXXXXIV]

The compound represented by the formula (469) is reacted with formalinin an appropriate solvent such as acetonitrile at from room temperatureto the reflux temperature in the presence of an appropriate reducingagent such as sodium borohydride or sodium borocyanohydride to therebygive a compound represented by the formula (474).

[Step XXXXVII]

The amine represented by the formula (469) is reacted with anappropriate sulfonic anhydride or acid halide optionally in anappropriate solvent such as dichloromethane in the presence of anappropriate base such as pyridine, triethylamine orN,N-diisopropylethylamine to thereby give a compound represented by theformula (473).

[Step LII]

The compound represented by the formula (469) is reacted with sodiumisocyanate, potassium isocyanate, etc. in a solvent such as water orethanol optionally in the presence of an appropriate acid such as aceticacid. Alternatively, it is reacted with trimethylsilyl isocyanate in adry solvent such as tetrahydrofuran in the presence of a base such astriethylamine at from room temperature to the reflux temperature tothereby give a compound represented by the formula (471).

[Step L]

The compound represented by the formula (469) is reacted with anappropriate isocyanate in an appropriate solvent to thereby give acompound represented by the formula (472). As the solvent, use can bemade of tetrahydrofuran, toluene, etc. The reaction can be effected atfrom room temperature to the reflux temperature of the solvent.

wherein G, Z, Q, E, X², l², R and R^(m) are each as defined above.

[Step CXIII]

A compound represented by the formula (476) is reacted with phthalimidein an appropriate dry solvent such as tetrahydrofuran or dichloromethanein the presence of triphenylphosphine and diethyl diazodicarboxylate tothereby give a compound represented by the formula (477). The reactioncan be effected at from 0° C. to the reflux temperature.

[Step CXIV]

The compound represented by the formula (477) is reacted with hydrazinein an alcoholic solvent such as ethanol to thereby give an aminederivative represented by the formula (478). The reaction is effectedpreferably at from 50° C. to the reflux temperature.

wherein G, Q, Z, E, X², l², R, R′ and R^(d) are each as defined above.

[Step XXXXVI]

An amine represented by the formula (479) is reacted with a carboxylicanhydride and an acid halide optionally in an appropriate solvent in thepresence of an appropriate base such as pyridine, triethylamine orN,N-diisopropylethylamine to thereby give amides represented by theformulae (480) and (483). As the solvent, use can be made of drydichloromethane, dry tetrahydrofuran, etc. The reaction can be effectedat from 0° C. to the reflux temperature.

[Step CXV]

The amine represented by the formula (479) is heated under reflux inethyl formate to thereby give an amdie derivative represented by theformula (481).

[Step CXVI]

Benzoyl chloride is treated with ammonium thiocyanate in acetone. Thereagent thus obtained is then reacted with the amine represented by theformula (479) to thereby give a thiourea derivative represented by theformula (484).

[Step VIII]

A compound represented by the formula (484) is treated with anappropriate acid such as hydrochloric acid, trifluoroacetic acid oracetic acid optionally in an appropriate solvent such as dichloromethaneor tetrahydrofuran to thereby give an amine represented by the formula(485).

[Step XI]

The compound represented by the formula (485) is reacted with anappropriate base such as sodium hydroxide or potassium hydroxide in analcoholic solvent such as methanol or ethanol or an aqueous solvent suchas a solvent mixture of alcohol, tetrahydrofuran and water at from roomtemperature to the reflux temperature of the solvent to thereby give acompound represented by the formula (486).

wherein G, Q, Z, E, X², l², R′, R^(m) and L¹ are each as defined above.

[Step XXI]

A compound represented by the formula (487) is treated with anappropriate base such as sodium hydride or sodium methoxide in a solventsuch as dimethoxyethane, tetrahydrofuran or N,N-dimethylformamide andthen reacted with an appropriate alkyl halide to thereby give aderivative represented by the formula (488). The reaction can beeffected at from −100° C. to room temperature.

[Step L]

The compound represented by the formula (487) is reacted with anisocyanate in an appropriate solvent to thereby give a compoundrepresented by the formula (489). As the solvent, use can be made oftetrahydrofuran or toluene. The reaction can be effected at from roomtemperature to the reflux temperature of the solvent. It is sometimespreferable to effect the reaction in the presence of a base such aspyridine or triethylamine.

wherein G, Z, Q, E, X², l², R′, R^(a) and R^(c) are each as definedabove.

[Step CXVII]

an aldehyde represented by the formula (108) is reacted with atrihalomethane such as tribromoethane in an aqueous solvent mixture suchas water/1,4-dioxane at from 0° C. to room temperature in the presenceof a base such as potassium hydroxide or sodium hydroxide and lithiumchloride to thereby give a compound represented by the formula (490).

[Step III]

The compound represented by the formula (490) is reacted with analkylating agent such as methyl iodide in a dry solvent such asN,N-dimethylformamide or tetrahydrofuran at from 0 to 40° C. in thepresence of a base such as potassium carbonate to thereby give an esterrepresented by the formula (491).

[Step CXVIII]

The aldehyde represented by the formula (108) is reacted with ahaloacetic acid derivative such as methyl bromoacetate in an appropriatedry solvent such as dry tetrahydrofuran in the presence of trimethylborate and zinc dust to thereby give a compound represented by theformula (492).

[Step XXIV]

The compound represented by the formula (492) is treated with a reducingagent such as aluminum lithium hydride or lithium borohydride in asolvent such as dry tetrahydrofuran or dry diethyl ether to thereby givean amine of the formula (493). The reaction can be effected at from 0°C. to the reflux temperature.

wherein G, Q, Z, E, X², l², R′ and R^(a) are each as defined above.

[Step XIII]

The compound represented by the formula (108) is reacted with anappropriate Horner-Emmons reagent in a solvent in the presence of anappropriate base to thereby give a compound represented by the formula(494). As the solvent, use can be made of dry solvents such asN,N-dimethylformamide, tetrahydrofuran or diethyl ether. As the base,use can be made of sodium hydride, potassium tert-butoxide,n-butyllithium, lithium diisopropylamide, etc. The reaction can beeffected at from −100° C. to the reflux temperature of the solvent.

[Step XXIV]

The compound represented by the formula (494) is treated with a reducingagent such as aluminum lithium hydride or lithium borohydride in asolvent such as dry tetrahydrofuran or dry diethyl ether to thereby givean alcohol of the formula (495). The reaction can be-effected at from 0°C. to the reflux temperature.

[Step XIV]

The compound represented by the formula (495) is subjected to areduction reaction with the use of an appropriate metal catalyst in asolvent to thereby give a compound represented by the formula (496). Thereaction may be carried out in, for example, a solvent such as methanol,ethanol, ethyl acetate or tetrahydrofuran with the use of palladium,platinum (IV) oxide, etc. as the catalyst under normal to elevatedhydrogen pressure.

wherein G, Q, Z, E, X², l², R^(m), V¹, R′ and R^(a) are each as definedabove.

[Step XI]

A compound represented by the formula (105) is reacted with anappropriate base such as sodium hydroxide or potassium hydroxide in analcoholic solvent such as methanol or ethanol or an aqueous solvent suchas a solvent mixture of alcohol, tetrahydrofuran and water at from roomtemperature to the reflux temperature of the solvent to thereby give acompound represented by the formula (499).

[Step XVII]

The compound represented by the formula (497) is treated with hydrogenperoxide in a solvent such as ethanol or dimethyl sulfoxide or a mixturethereof in the presence of a base such as sodium hydroxide or potassiumhydroxide at from 0° C. to room temperature. Alternatively, it isreacted with an alkali such as sodium hydroxide or potassium hydroxidein a solvent such as dimethyl sulfoxide at from 50 to 100° C. to therebygive a compound represented by the formula (498).

[Step CXIX]

The amide represented by the formula (498) is treated with bromine inwater in the presence of a base such as sodium hydroxide or potassiumhydroxide to thereby give an amine represented by the formula (479).

[Step LXXXIX]

The ester represented by the formula (105) is treated with hydroxylaminehydrochloride in a solvent mixture such as tetrahydrofuran/water in thepresence of a base such as sodium hydroxide or potassium hydroxide tothereby give a compound represented by the formula (500).

[Step LXXXX]

The carboxylic acid represented by the formula (499) is reacted with anappropriate diimide, an appropriate chloroformate, an appropriatedichlorophosphonate or carbonyldiimidazole at from 0 to 60° C. in anappropriate dry solvent such as N,N-dimethylformamide, tetrahydrofuran,acetonitrile or dichloromethane optionally in the presence of anappropriate base such as pyridine, triethylamine orN,N-diisopropylethylamine. The activated ester thus obtained is thenreacted with ammonia or an appropriate amine or amine derivative tothereby give amides represented by the formulae (498), (501) and (502).

wherein G, Z, Q, E, X², l² and R′ are each as defined above.

[Step XIII]

The compound represented by the formula (108) is reacted with anappropriate Horner-Emmons reagent in a solvent in the presence of anappropriate base to thereby give a compound represented by the formula(503). As the solvent, use can be made of dry solvents such asN,N-dimethylformamide, tetrahydrofuran or diethyl ether. As the base,use can be made of sodium hydride, potassium tert-butoxide,n-butyllithium, lithium diisopropylamide, etc. The reaction can beeffected at from −100° C. to the reflux temperature of the solvent.

[Step LXXXVII]

The nitrile represented by the formula (503) is treated with anazidation agent such as sodium azide in a dry solvent such as dimethylsulfoxide, N,N-dimethylformamide or 1-methyl-2-pyrrolidone at from 50°C. to the reflux temperature to thereby give a tetrazole derivativerepresented by the formula (504)

[Step CXXI]

In a dry solvent such as tetrahydrofuran, (tirmethylsilyl)dizaomethaneis treated with a strong base such as n-butyllithium at from −100° C. toroom temperature. The anion thus obtained is reacted with the compoundof the formula (503) to thereby give a pyrazole derivative representedby the formula (505).

[Step LI]

The compound represented by the formula (505) is treated with a reagentsuch as tetra-n-butylammonium fluoride or caesium fluoride in a drysolvent such as tetrahydrofuran to thereby give a compound representedby the formula (506).

[Step LXV]

An aldehyde derivative represented by the formula (108) is reacted withhydroxylamine in a solvent such as ethanol or tetrahydrofuran in thepresence of a catalyst such as sodium acetate or ammonium acetate tothereby give an oxime represented by the formula (507). This reactioncan be effected at from room temperature to the reflux temperature.

[Step CXX]

The oxime represented by the formula (507) is heated under reflux intrifluoroacetonitrile to thereby give a nitrile represented by theformula (497).

[Step LXXXVII]

The nitrile represented by the formula (497) is treated with anazidation agent such as sodium azide in a dry solvent such as dimethylsulfoxide, N,N-dimethylformamide or 1-methyl-2-pyrrolidone at from 50°C. to the reflux temperature in the presence of a catalyst such asammonium chloride to thereby give a tetrazole derivative represented bythe formula (508).

[Step CXXII]

The aldehyde represented by the formula (108) is reacted with2-aminoethanethiol in an alcoholic solvent such as methanol in thepresence of a base such as sodium methoxide at from room temperature tothe reflux temperature to thereby give a compound represented by theformula (509).

wherein G, Z, Q, E, X², l², Hal, R^(m), R^(k) and R are each as definedabove.

[Step XXVIII]

A halide represented by the formula (510) is treated with a cyanidationreagent such as sodium cyanide or potassium cyanide in an appropriatesolvent such as dimethyl sulfoxide to thereby give a nitrile compoundrepresented by the formula (511). The reaction can be effected at fromroom temperature to 100° C.

[Step CV]

The nitrile represented by the formula (511) is reacted with sodiumhydrosulfide and hydrogen sulfide in an appropriate solvent such asmethanol at from −30 to 100° C. under elevated pressure to thereby givea thioamide represented by the formula (512).

[Step CXXIII]

The thioamide represented by the formula (512) is reacted with anappropriate α-halocarbonyl derivative in an appropriate solvent mixturesuch as tetrahydrofuran/dimethoxyethane or ethanol/N,N-dimethylformamideat from room temperature to 100° C. optionally in the presence of anappropriate base such as potassium hydrogencarboante or sodiumhydrogencarbonate to thereby give compounds represented by the formulae(513) and (514).

[Step CXXIV]

The compound represented by the formula (513) is reacted with anappropriate acid anhydride such as trifluoroacetic anhydride, an acidhalide, etc. in an appropriate solvent such as dimethoxyethane in thepresence of an appropriate base such as pyridine to thereby give athiazole represented by the formula (514).

[Step CXXV]

The thioamide represented by the formula (512) is reacted with hydrazinein an appropriate solvent such as tetrahydrofuran or ethanol or amixture thereof at from room temperature to the reflux temperature. Theintermediate thus obtained is treated with an appropriate orthoester inan appropriate solvent such as tetrahydrofuran or ethanol or a mixturethereof at from room temperature to the reflux temperature to therebygive a compound represented by the formula (515).

wherein G, Z, Q, E, X², l², Nu and R′ are each as defined above.

[Step CXXVI]

An aldehyde represented by the formula (108) is treated with atosylmethylisocyanide in an appropriate alcoholic solvent such asmethanol or ethanol in the presence of an appropriate base such aspotassium carbonate or sodium carbonate to thereby give an oxazolerepresented by the formula (516). The reaction can be effected at fromroom temperature to the reflux temperature of the solvent.

[Step CXXVII]

The aldehyde represented by the formula (108) is reacted with anappropriate secondary amine in pyridine to thereby give a compoundrepresented by the formula (517). The reaction is effected preferably atfrom 50° C. to the reflux temperature.

[Step XXXXIV]

The imine represented by the formula (517) is heated under reflux inpyridine in the presence of oxygen to thereby give a cyclized productrepresented by the formula (518).

wherein G, Z, Q, E, X², l², Nu and R′ are each as defined above.

[Step XVI]

The ketone compound represented by the formula (519) is treated with astrong base such as lithium diisopropylamide in a dry solvent such astetrahydrofuran or diethyl ether. Then the anion thus obtained istreated with an acetylation agent such as acetic anhydride or acetylchloride to thereby give a diketone compound represented by the formula(520).

[Step CXIV]

The compound represented by the formula (520,) is reacted with hydrazineor hydroxylamine in an alcoholic solvent such as methanol or ethanol tothereby give a compound represented by the formula (521). The reactioncan be effected preferably at from 50° C. to the reflux temperature.

wherein G, Z, Q, E, X², l², Hal and R′ are each as defined above.

[Step LXXXIX]

An acid halide represented by the formula (522) is treated with2-aminopyridine optionally in an appropriate solvent such asdichloromethane, methanol or tetrahydrofuran or a solvent mixture suchas ethanol/tetrahydrofuran in the presence of an appropriate base suchas sodium hydrogencarbonate, pyridine, triethylamine orN,N-diisopropylethylamine to thereby give a compound represented by theformula (523). The reaction can be effected at from 0° C. to the refluxtemperature.

[Step CXXVIII]

The ketone compound represented by the formula (523) is treated withthionyl chloride in an appropriate dry solvent such as carbontetrachloride at from room temperature to the reflux temperature tothereby give a compound represented by the formula (524).

[Step CXXIII]

The haloketone represented by the formula (522) is reacted with anappropriate thioamide derivative or thioimidate in an appropriatesolvent mixture such as tetrahydrofuran/dimethoxyethane orethanol/N,N-dimethylformamide at from room temperature to 100° C.optionally in the presence of an appropriate base such as potassiumhydrogencarbonate or sodium hydrogencarbonate to thereby give compoundsrepresented by the formulae (525) and (526).

wherein G, Z, Q, E, X² and l² are each as defined above.

[Step XXXXIV]

An amine represented by the formula (527) is heated in an appropriatesolvent to thereby give a triazole derivative represented by the formula(528). As the solvent, use can be made of dry N,N-dimethylformamide,etc. The reaction is effected preferably at from 50 to 150° C.

wherein B¹ and R′ are each as defined above.

[Step XXXXII]

A compound represented by the formula (530) is treated with a base suchas sodium hydride and then reacted with a halogen compound (529) in asolvent such as dry N,N-dimethylformamide or tetrahydrofuran to therebygive a compound represented by the formula (531).

[Step XXXXIII]

The nitro compounds represented by the formulae (531) and (535) aretreated with a reducing agent such as iron in a solvent mixture of analcohol, tetrahydrofuran and water in the presence of ammonium chloride.Alternatively, it is treated with sodium hydrosulfite in a solventmixture of tetrahydrofuran with water. Thus, compounds represented bythe formulae (532) and (536) can be produced respectively. As thealcohol, use can be made of methanol, ethanol, isopropanol etc.

[Step VII]

The amines represented by the formulae (532) and (534) are treated witha base such as sodium hydride and a protecting reagent such asmethoxymethyl chloride in a solvent such as N,N-dimethylformamide tothereby give compounds represented by the formulae (533) and (535)respectively.

[Step XXI]

The compounds represented by the formulae (534) and (536) are treatedwith a base such as sodium hydride and an appropriate alkylating agentin a dry solvent such as N,N-dimethylformamide to thereby give compoundsrepresented by the formulae (531) and (537) respectively.

wherein G, Z, Q, E, X², l² and R′ are each as defined above.

[Step CXXIX]

An alkene represented by the formula (538) is treated with osmiumtetraoxide in a solvent such as acetone or tert-butanol or a mixturethereof in the presence of an oxidizing agent such asN-methyl-morpholine to thereby give a diol represented by the formula(539).

[Step XXXXIII]

The nitro compound represented by the formula (539) is treated with areducing agent such as iron in a solvent mixture of an alcohol,tetrahydrofuran and water in the presence of ammonium chloride.Alternatively, it is treated with sodium hydrosulfite in a solventmixture of tetrahydrofuran with water. Thus, a compound represented bythe formula (540) can be produced. As the alcohol, use can be made ofmethanol, ethanol, isopropanol, etc.

wherein R^(k) is as defined above.

[Step XIV]

The compound represented by the formula (541) is subjected to areduction reaction with the use of an appropriate metal catalyst in asolvent to thereby give a compound represented by the formula (542). Thereaction may be carried out in, for example, a solvent such as methanol,ethanol, ethyl acetate or tetrahydrofuran with the use of palladium,platinum (IV) oxide, etc. as the catalyst under normal to elevatedhydrogen pressure.

wherein G, Z, Q, E, X², l², M, R^(a) and R′ are each as defined above.

[Step XXIV]

A compound represented by the formula (543) is treated with a reducingagent such as aluminum lithium hydride or lithium borohydride in asolvent such as dry tetrahydrofuran or dry diethyl ether to thereby givean alcohol of the formula (544). The reaction can be effected at from 0°C. to the reflux temperature.

wherein G, Z, Q, E, X², l², M, R^(k), R¹ and R′ are each as definedabove.

[Step LXXXIX]

A halide represented by the formula (545) is treated with an appropriateamine in an appropriate alcoholic solvent such as methanol or ethanol tothereby give an amine derivative represented by the formula (546). Thereaction can be effected at from room temperature to the refluxtemperature.

[Step XXXXIII]

The nitro compound represented by the formula (546) is treated with areducing agent such as iron in a solvent mixture of an alcohol,tetrahydrofuran and water in the presence of ammonium chloride.Alternatively, it is treated with sodium hydrosulfite in a solventmixture of tetrahydrofuran with water. Thus, a compound represented bythe formula (547) can be produced. As the alcohol, use can be made ofmethanol, ethanol, isopropanol, etc.

wherein G, Z, Q, E, X², l², M, L¹ and R′ are each as defined above.

[Step XXXXVII]

An amine represented by the formula (548) is reacted with an appropriatesulfonic anhydride or acid halide optionally in an appropriate solventsuch as dichloromethane in the presence of an appropriate base such aspyridine, triethylamine or N,N-diisopropylethylamine to thereby give acompound represented by the formula (549).

[Step LXXIX]

The sulfonic acid derivative represented by the formula (549) is treatedwith an appropriate sulfonamide in a dry solvent such as tetrahydrofuranor N,N-dimethylformamide in the presence of a strong base such as sodiumhydride or lithium diisopropylamide at from 0 to 100° C. to thereby givea compound represented by the formula (550).

wherein G, Z, Q, E, X², l², M, Hal and R′ are each as defined above.

[Step XXI]

A compound represented by the formula (551) is treated with a base suchas sodium hydride and an appropriate alkylating agent in a dry solventsuch as N,N-dimethylformamide to thereby give a compound represented bythe formula (552).

[Step LXXXVII]

The nitrile represented by the formula (552) is treated with anazidation agent such as sodium azide in a dry solvent such as dimethylsulfoxide, N,N-dimethylformamide or 1-methyl-2-pyrrolidone at from 50°C. to the reflux temperature to thereby give an azide represented by theformula (553).

[Step XIV]

The compound represented by the formula (553) is subjected to areduction reaction with the use of an appropriate metal catalyst in asolvent to thereby give a compound represented by the formula (555). Thereaction may be carried out in, for example, a solvent such as methanol,ethanol, ethyl acetate or tetrahydrofuran with the use of palladium,platinum (IV) oxide, etc. as the catalyst under normal to elevatedhydrogen pressure.

[Step CXIII]

The compound represented by the formula (552) is reacted withphthalimide in an appropriate dry solvent such as tetrahydrofuran ordichloromethane in the presence of triphenylphosphine and diethyldiazodicarboxylate to thereby give a compound represented by the formula(554). The reaction can be effected at from 0° C. to the refluxtemperature.

[Step CXIV]

The compound represented by the formula (554) is reacted with hydrazinein an alcoholic solvent such as ethanol to thereby give an aminederivative represented by the formula (555). The reaction is effectedpreferably at from 50° C. to the reflux temperature.

[Step XXXXVII]

The amine represented by the formula (555) is reacted with anappropriate sulfonic anhydride or acid halide optionally in anappropriate solvent such as dichloromethane or N,N-dimethylformamide inthe presence of an appropriate base such as pyridine, triethylamine orN,N-diisopropylethylamine to thereby give a compound represented by theformula (556).

[Step CXXX]

The amine represented by the formula (555) is reacted withformamidinesulfonic acid or an appropriate methylisothiourea derivativein an appropriate alcoholic solvent such as methanol at from 0° C. tothe ref lux temperature to thereby give a compound represented by theformula (557).

[Step LII]

The compound represented by the formula (555) is reacted with sodiumisocyanate, potassium isocyanate, etc. in a solvent such as water orethanol optionally in the presence of an appropriate acid such as aceticacid. Alternatively, it is reacted with trimethylsilyl isocyanate in adry solvent such as tetrahydrofuran in the presence of a base such astriethylamine at from room temperature to the reflux temperature tothereby give a compound represented by the formula (558).

[Step XXXXVI]

An amine represented by the formula (555) is reacted with a carboxylicanhydride, a carboxylic phosphoric anhydride or an acid halideoptionally in an appropriate solvent in the presence of an appropriatebase such as pyridine, triethylamine or N,N-diisopropylethylamine tothereby give an amide represented by the formula (559). As the solvent,use can be made of dry N,N-dimethylformamide, dry dichloromethane, etc.The reaction can be effected at from 0° C. to the reflux temperature.

wherein G, Z, Q, E, X², l² and R′ are each as defined above.

[Step LXX]

The nitrile compound represented by the formula (497) is treated withdiisobutylaluminum hydride in an appropriate solvent such as toluene ordichloromethane to thereby give an aldehyde compound represented by theformula (108). The reaction temperature preferably ranges from −100° C.to room temperature.

wherein G, Z, Q, E, X², l² and R′ are each as defined above.

[Step XXXII]

Methyltriphenylphosphonium bromide is reacted with an appropriate basesuch as potassium tert-butoxide or butyllithium in a solvent such asN,N-dimethylformamide, toluene, xylene or tetrahydrofuran followed by areaction with an aldehyde represented by the formula (108). Thus acompound represented by the formula (560) can be obtained. The reactiontemperature preferably ranges from room temperature to 100° C.

[Step CXXIX]

The alkene represented by the formula (560) is treated with osmiumtetraoxide in a solvent such as acetone or tert-butanol or a mixturethereof in the presence of an oxidizing agent such as N-methylmorpholineoxide to thereby give a diol represented by the formula (561).

wherein G, Z, Q, E, X², l², Hal, Ar and R′ are each as defined above.

[Step CXXXI]

A halide represented by the formula (562) is reacted with an appropriatearylcopper complex or heteroarylcopper complex in a dry solvent such astoluene or N,N-dimethylformamide in the presence of triphenylphosphineto thereby give a compound represented by the formula (563).

wherein G, Z, Q, E, X², l², R^(a), R^(d) and R′ are each as definedabove.

[Step LXXXIX]

An alkyne compound represented by the formula (564) is treated with anappropriate amine such as dimethylamine in an appropriate alcoholicsolvent such as methanol or ethanol to thereby give a ketone compoundrepresented by the formula (565). The reaction can be effected at fromroom temperature to the reflux temperature.

[Step LXXXXIII]

The α,β-alkynyl ester compound represented by the formula (564) istreated with sodium thiomethoxide in a solvent mixture ofN,N-dimethylformamide with methanol to thereby give a compoundrepresented by the formula (566). The reaction is effected preferably atfrom 0° C. to room temperature.

[Step LXIX]

A sulfide compound represented by the formula (566) is treated with aperoxide such as 3-chloroperbenzoic acid in an appropriate solvent suchas dichloromethane in the presence of sodium carbonate, etc. to therebygive a sulfoxide compound represented by the formula (567). The reactiontemperature preferably ranges from room temperature to 40° C.

wherein G, Z, Q, E, X² and l² are each as defined above.

[Step XXI]

A thiourea compound represented by the formula (486) is treated with anappropriate methylating agent such as methyl iodide in a solvent such asacetone to thereby give a methyliosthiourea derivative represented bythe formula (568).

[Step LXXXIX]

The thiourea compound represented by the formula (568) is treated withcyanamide in a dry solvent such as tetrahydrofuran orN,N-dimethylformamide to thereby give a compound represented by theformula (569). The reaction is effected preferably at from 50 to 100° C.

wherein G, Z, Q, E, X² and l² are each as defined above; and V⁴represents nitro or methylsulfonyl.

[Step CXXX]

An amine represented by the formula (570) is reacted withformamidinesulfonic acid or an appropriate methylisothiourea derivativein an appropriate alcoholic solvent such as methanol at from 0° C. tothe reflux temperature to thereby give compounds represented by theformulae (571) and (572).

wherein G, Z, Q, E, X² and l² are each as defined above.

[Step CXXXII]

An aldehyde represented by the formula (104) is reacted with anappropriate cyanidation agent such as sodium cyanide or potassiumcyanide in a solvent mixture of ethanol with water at from roomtemperature to the reflux temperature to thereby give an amidinecompound represented by the formula (573).

wherein G, Z, Q, E, R^(d), Hal, X² and l² are each as defined above.

[Step CXXXIII]

A halide represented by the formula (574) is heated in an appropriatetrialkyl phosphite to thereby give a dialkyl phosphonate represented bythe formula (575). The reaction is effected preferably at from 100 to200° C.

wherein G, Z, Q, E, R′, Hal, X²and l² are each as defined above.

[Step CXXXIV]

A halide represented by the formula (352) is reacted with sodium sulfitein a solvent mixture of an appropriate alcohol such as methanol withwater at from room temperature to the reflux temperature to thereby givea sulfonic acid derivative represented by the formula (576).

wherein R^(d) is as defined above.

[Step LXXXV]

A nitrile compound represented by the formula (577) is treated with anappropriate acid in an alcoholic solvent to thereby give an imidaterepresented by the formula (578) (i.e., the so-called Pinner reaction).It is preferable to use hydrochloric acid as the acid. The reaction ispreferably effected in methanol/dichloromethane at from 0 to 10° C.

[Step LXXXVI]

The imidate represented by the formula (578) is reacted with an amine oran amide in an appropriate solvent to thereby give a compoundrepresented by the formula (579). Acetonitrile or a mixture ofacetonitrile with methanol may be cited as the most desirable solvent.The reaction is effected preferably at from room temperature to 40° C.

wherein G, Z, E, R′, R^(a), X², and l² are each as defined above.

[Step XXIX]

A compound represented by the formula (580) is reacted with a reducingagent such as sodium borohydride in a solvent to thereby give a compoundrepresented by the formula (581). As the solvent, use can be made ofmethanol, ethanol, etc. The reaction can be effected at from 0° C. tothe reflux temperature.

[Step LXIX]

A sulfide compound represented by the formula (582) is treated with aperoxide such as 3-chloroperbenzoic acid in an appropriate solvent suchas dichloromethane in the presence of sodium carbonate, etc.Alternatively, it is treated with hydrogen peroxide in acetic acid.Thus, a sulfoxide compound represented by the formula (583) can beobtained. The reaction temperature preferably ranges from roomtemperature to 40° C.

Production Process 8

wherein the ring G, E, Z, R′ and U¹ are as defined above.

(Step 1)

This step comprises protecting the hydroxyl group of a compoundrepresented by the general formula (584) to thereby give a compoundrepresented by the general formula (585). Although the protective groupis nonlimitative and any arbitrary group may be used so long as it isknown as a hydroxyl protective group in organic synthesis, preferableexamples thereof are alkylsilyl groups such as trimethylsilyl,isopropyldimethylsilyl, tert-butyldimethylsilyl andtert-butyldiphenylsilyl. When the protective group is an alkylsilylgroup, the reaction is conducted by treating a compound (584) with analkylsilyl chloride such as tert-butyldimethylsilyl chloride at atemperature of −50 to 50° C. in a solvent such as N,N-dimethylformamide,N,N-dimethylacetamide, tetrahydrofuran or dioxane in the presence of abase such as imidazole, pyridine or dimethylpyridine.

(Step 2)

This step comprises introducing a lower alkyl group, optionallysubstaituted arylalkyl gorup, optionally substituted heteroaryl group,amino protective group, group represented by —X³—NR⁹R¹⁰; wherein X³, R⁹and R¹⁰ are as defined above, group represented by —X⁴—CO₂R¹¹; whereinX⁴ and R¹¹ are as defined above, into the NH group of the compoundrepresented by the general formula (585). The reaction is conducted inthe conventional method.

(Step 3)

This step comprises eliminating the hydroxyl protective group of thecompound represented by the general formula (586). When the protectivegroup is an alkylsilyl group, this reaction is conducted by usingpotassium carbonate/methanol, acetic acid/water, boron trifluorideetherate/chloroform, tetra-n-butylammonium chloride/potassiumfluoride/acetonitrile, or tetra-n-butylammonium fluoride/dioxane ortetrahydrofuran, among which preferred is tetra-n-butylammoniumfluoride/tetrahydrofuran. The reaction temperature ranges from 0 to 50°C.

(Step 4)

This step comprises oxidizing the hydroxymethyl group of the compoundrepresented by the general formula (587) to thereby give an aldehyderepresented by the general formula (588). The aldehyde is obtained byadding a solution of the alcohol represented by the formula (587) in asolvent such as methylene chloride to a liquid reaction mixture preparedfrom oxalyl chloride and dimethyl sulfoxide and treating the resultantmixture with a base such as triethylamine, by treating the abovesolution of the alcohol with pyridinium dichromate in a solvent such asdichloromethane or N,N-dimethylformamide, or by treating the abovesolution with manganese dioxide in a solvent such as dichloromethane.

(Step 5)

This step comprises conducting a reductive amination by treating thecompound represented by the formula (588) with a secondary amine in thepresence of a reducing agent.

The reaction of the aldehyde reprsented by the formula (588) with thesecondary amine is conducted in an appropriate solvent such as tolueneor benzene at room temperature to the solvent reflux temperature andtreating the intermediate thus obtained with an appropriate reducingagent such as sodium borohydride or sodium boron cyanohydride in anappropriate alcoholic solvent such as ethanol or methanol or anappropriate solvent mixture such as ethanol/tetrahydrofuran at atemperature of 50° C. to the solvent reflux temperature to therebyobtain the compound represented by the formula (589).

The compounds of the present invention can be easily produced by theabove-mentioned production processes or publicly known processes.

The solvent usable in the present invention described above may be anarbitrary one without restriction so long as it doesn't inhibit thereaction and has been employed commonly in organic synthesis. Examplesthereof include lower alcohols such as methanol, ethanol, propanol andbutanol; polyalcohols such as ethylene glycol and glycerol; ketones suchas acetone, methyl ethyl ketone, diethyl ketone and cyclohexanone;ethers such as diethyl ether, isopropyl ether, tetrahydrofuran, dioxane,2-methoxyethanol and 1,2-dimethoxyethane; nitriles such as acetonitrileand propionitrile; esters such as methyl acetate, ethyl acetate,isopropyl acetate, butyl acetate and diethyl phthalate; halogenatedhydrocarbons such as dichloromethane, chloroform, carbon tetrachloride,1,2-dichloroethane, trichloroethylene and tetrachloroethylene; aromaticsolvents such as benzene, toluene, xylene, monochlorobenzene,nitrobenzene, indene, pyridine, quinoline, collidine and phenol;hydrocarbons such as pentane, cyclohexane, hexane, heptane, octane,isooctane, petroleum benzene and petroleum ether; amines such asethanolamine, diethylamine, triethylamine, pyrrolidine, piperidine,piperazine, morpholine, aniline, dimethylaniline, benzylamine andtoluidine; amides such as formamide, N-methylpyrrolidone,N,N-dimethylimidazolone, N,N-dimethylacetamide andN,N-dimethylformamide; phosphoramides such as hexamethylphosphorictriamide and hexamethylphosphorous triamide; water, other solventscommonly employed in the art and mixtures thereof. The mixing ratio isnot particularly restricted.

The base to be used in the present invention, partially above described,may be an arbitrary one without restriction so long as it has been wellknown as a base for organic synthesis and as it doesn't inhibit thereaction. Examples thereof include sodium carbonate, sodiumhydrogencarbonate, potassium carbonate, sodium hydride, potassiumhydride, t-butoxypotassium, pyridine, dimethylaminopyridine,trimethylamine, triethylamine, N,N-diisopropylethylamine,N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine,N,N-dimethylaniline, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine,4-dimethylaminopyridine, picoline, lutidine, quinoline, isoquinoline,sodium hydroxide, potassium hydroxide, lithium hydroxide, butyllithiumand, sodium and potassium alcoholates such as sodium methylate andpotassium methylate.

As the halogenation agent, use can be made of an arbitrary one commonlyemployed in the synthesis of acid halides. Examples thereof includephosgene, diphosgene (phosgene dimer), triphosgene (phosgene trimer),thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorustribromide, phosphorus oxychloride, phosphorus pentachloride,trichloromethyl chloroformate, oxalyl chloride and Vilsmeier reagentsobtained by treating acid amides or phosphoramide with thesehalogenation agents.

The reducing agent is not particularly restricted but may be anarbitrary one commonly employed in organic synthesis. Examples thereofinclude NaBH₄, LIBH₄, Zn(BH₄)₂, Me₄NBH (OAc )₃, NaBH₃CN, Selctride,Super Hydride (LiBHEt₃), LiAlH₄, DIBAL, LiAlH(t-BuO)₃, Red-al, binap,and catalytic hydrogenation catalysts of platinum, palladium, rhodium,ruthenium, nickel, etc.

After the completion of these reactions, the products may be purified byconventional procedures, for example, column chromatography with the useof silica gel, adsorbent resins, etc. or recrystallization fromappropriate solvents, if desired.

To illustrate the usefulness of the present invention, the followingpharmacological experimental examples will be given.

EXPERIMENTAL EXAMPLE 1

Effect on the Expression of ICAM-1 in Human Cultured Umbilical CordEndothelial Cells

Examination was made on the effect on the expression of ICAM-1 which isone of adhesion molecules expressed on the surfaces of culturedendothelia cells. The endotheliall cells were suspended in an MCDB131medium containing 10% of fetal calf serum and pipetted into a 96-wellculture plate (10,000 cells/well). After culturing at 37° C. in thepresence of 5% of carbon dioxide for 2 days, 1 ng/ml of a tumor necrosisfactor (TNF) and a test compound were added to the 96-well cultureplate. After culturing at 37° C. in the presence of 5% of carbon dioxidefor 4 hours and then washing with a phosphate buffer once, 0.05% ofglutaraldehyde was added thereto. Six minutes thereafter, the plate waswashed twice and 1 μg/ml of a mouse antihuman ICAM-1 antibody was addedthereto. After allowing to stand for 1 hour, it was washed twice and aperoxidase-labeled sheep antimouse immunoglobulin antibody was addedthereto. After allowing to stand for 1 hour, it was washed twice and acolor developing substrate for peroxidase (o-phenylenediamine) was addedthereto. After allowing to stand at room temperature for 10 minutes, a 1N solution of sulfuric acid was added thereto. Then the absorbance at490 nm was measured with the use of an absorptiometer for 96-well plate.The value thus obtained was employed as an indication of the ICAM-1expression.

The following Table 1 shows the 50% inhibitory concentrations (IC₅₀; μM)calculated by taking the expression dose under the addition of TNF as100% and that under the addition of no TNF as 0%.

TABLE 1 Compd. IC₅₀ (Ex. No.) (μM) 15 2.3 18 3.5 23 1.6 24 4.1 30 0.5 311.1 70 2.8 71 0.8 73 0.6 74 1.9 75 2.4 77 2.8 78 1.4 78 0.5 80 4.1 823.4 83 2.8 85 6.4 87 2.9 88 2.6 89 2.8 90 2.8 91 2.9 98 2.4 100 3.8 1012.6 102 2.6 103 6.6 104 2.8 105 5.8 106 2.8 107 3.3 113 2.5 118 1.6 1217.4 402 0.32 403 0.34 460 0.32 659 0.71 677 0.90 686 0.90 698 0.49 7171.15 729 1.30 901 1.8 1145 0.77 1241 3.6 1409 0.67 1439 0.49 1487 0.671568 0.5

EXPERIMENTAL EXAMPLE 2

Effect on Carrageenin-induced Rat Pleurisy

200 μl of a carrageenin solution (10 mg/ml in physiological saline) wasintrathoracically injected into rats. Five hours thereafter, blood ofthe animals was collected from the abdominal aorta under etherization soas to induce death from blood loss. The exudate was taken up from thethoracic cavity and weighed with a single-pan balance. Further, theexudate was diluted with Turk's solution and the cells were counted byusing a counting chamber. Next the total cell count was calculated bymultiplying the cell count by the exudate volume. Thus the inhibitoryratio was calculated by taking the total cell count with theadministration of carrageenin as 100% and that with the administrationof physiological saline as 0%. Each test compound was suspended in a0.5% solution of methylcellulose and orally administered at a dose of 5ml/kg 30 minutes before the injection of carrageenin. Table 2 shows theresults.

TABLE 2 Compd. Inhibi- (Ex. Dose tory Compd. Dose Inhibitory No.)(mg/kg) ratio (%) (Ex. No.) (mg/kg) ratio (%) 15 10 64 121 10 70 18 1067 402 10 57 23 10 52 403 10 35 24 10 54 460 10 57 30 10 85 659 10 20 3110 38 677 10 76 71 10 94 686 10 71 73 10 74 698 10 26 79 10 44 717 10 3283 10 34 729 10 64 88 10 65 901 30 38 89 10 83 1145 10 29 91 10 76 1241100 28 98 10 30 1439 30 77 101 10 48 1487 30 32 106 10 46 1568 30 50

As described above, the compounds of the present invention haveexcellent anti-immune effect and, therefore, are highly useful aspreventives and remedies for inflammatory immune diseases or autoimmunediseases, in particular, as preventives and remedies for rheumatism,atopic dermatitis, psoriasis, asthma and the rejection reactionaccompanying organ transplantation.

As the above experimental examples show, the compounds of the presentinvention inhibit the functions of adhesion molecules and thus exhibitanti-immune and anti-inflammatory effects. Accordingly, they are usefulas preventives and remedies for inflammatory immune diseases such asinflammation, ischemic reflow disorders and the rejection reactionaccompanying organ transplantation, autoimmune diseases such asrheumatism and collagen disease and cancer metastasis. Moreparticularly, these compounds are useful as preventives and remedies forasthma, nephritis, ischemic reflow disorders, psoriasis, atopicdermatitis, rheumatism, collagen disease, the rejection reactionaccompanying organ transplantation and cancer metastasis.

Of them, particularly useful compounds are as follows:

1) (endo,syn)-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]non-9-yl]aceticacid;

2) (endo,anti)-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]non-9-yl]aceticacid;

3)(+)-(anti)-(6R*,7R*)-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-6,7-dimethyl-3-azabicyclo[3.2.1]oct-8-yl]aceticacid;

4)(−)-(anti)-(6R*,7R*)-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-6,7-dimethyl-3-azabicyclo[3.2.1]oct-8-yl]aceticacid;

5)(+)-(anti)-(6R*,8R*)-2-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-6,8-dimethyl-3-azabicyclo[3.3.1]non-9-yl]propanoicacid; and

6)(−)-(anti)-(6R*,8R*)-2-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-6,8-dimethyl-3-azabicyclo[3.3.1]non-9-yl]propanoicacid.

EXAMPLES

To further illustrate the present invention in greater detail, and notby way of limitation, the following Examples will be given.

Example 1 Methyl 10H-pyrazino[2,3-b][1,4]benzothiazine-8-carboxylate

600 g of sodium sulfide nonahydrate and 80 g of flower of sulfur washeated to prepare a homogeneous solution of disodium disulfide. To asuspension of 4-chloro-3-nitrobenzoic acid in ethanol (2,250 ml) wasadded a solution of 67 g of sodium hydroxide in water (125 ml). To themixture obtained was added the solution prepared above under stirringand the resulting mixture was heated under reflux for 30 minutes. Next,the reaction mixture was brought back to room temperature and thecrystals formed were taken up by filtration and air-dried to therebygive 450 g of dark green powdery crystals. By repeating the sameprocedure, 4.67 kg of dark green crystals were obtained from 5.20 kg of4-chloro-3-nitrobenzoic acid.

500 g of the crystals thus obtained and 1220 g of tin dust weresuspended in 2,800 ml of ethanol and conc. hydrochloric acid was addeddropwise thereinto until the reaction was completed. After completion ofthe reaction, the tin residue was eliminated and the solvent was reducedto a small volume through distillation under reduced pressure. Afteradding conc. hydrochloric acid and ethanol to the residue, the crystalsthus precipitated were taken up by filtration and air-dried to therebygive 300 g of a pale yellow powder. By repeating the same procedure,2.79 kg of the product was obtained from 4.67 kg of the startingmaterial. 2,400 ml of methanol was saturated with hydrogen chloride gasand 800 g of the above-mentioned pale yellow powder was added thereto.After heating under reflux for 7 hours, the solvent was completelydistilled off to dryness to thereby give 950 g of pale yellow crystals.By repeating the same procedure, 3.70 kg of the product was obtainedfrom 2.79 kg of the starting material.

1.0 kg of the crystals obtained were suspended in 1000 ml ofN,N-dimethylformamide and 800 g of 2,3-dichloropyrazine was addeddropwise thereinto with stirring. After the completion of the addition,the mixture was further reacted at 100° C. for 30 minutes and thenbrought back to room temperature. After adding 2 l of water to thereaction system, the crystals thus precipitated were taken up byfiltration and washed successively with water and diethyl ether tothereby give 400 g of the title compound as a yellow powder.

¹H-NMR(DMSO-d₆) δ ppm; 3.78(s, 3H), 7.02(d, J=8.2 Hz, 1H), 7.29(dd,J=1.9, 8.2 Hz, 1H), 7.31(d, J=1.9 Hz, 1H), 7.64(d, J=2.9 Hz, 1H),7.65(d, J=2.9 Hz, 1H), 9.63(s, 1H)

m.p.: 265-268° C.

MS: FAB(+)259(M⁺)

Example 2 10H-Pyrazino[2,3-b][1,4]benzothiazine-8-methanol

259 g of methyl 10H-pyrazino[2,3-b][1,4]benzothiazine-8-carboxylate wasdissolved in a solvent mixture of 3 l of methylene chloride with 0.5 lof tetrahydrofuran under a nitrogen atmosphere. Next, 2.5 l of a 1.01 Msolution of diisobutylaluminum hydride in toluene was added dropwisethereinto while cooling the mixture so as to maintain the temperature inthe system at 15° C. or below. After the completion of the reaction, thereaction mixture was poured into a mixture of 5 kg of ice with 3 l ofmethylene chloride. After adding 5 l of tetrahydrofuran, the resultingmixture was stirred for 1 hour. Then it was filtered and the filtratewas washed with water. After distilling off the solvent under reducedpressure, the obtained crystals were washed with diisopropyl ether tothereby give 125 g of the title compound as yellow crystals.

¹H-NMR(DMSO-d₆δ ppm; 4.30(d, J=6.0 Hz, 2H), 5.17(t, J=6.0 Hz, 1H),6.70(d, J=7.9 Hz, 1H), 6.75(s, 1H), 6.83(d, J=7.9 Hz, 1H), 7.61(d, J=2.6Hz, 1H), 7.63(d, J=2.6 Hz, 1H), 9.50(s, 1H)

m.p.: 187-189° C.

Example 3 10H-Pyrazino[2,3-b][1,4]benzothiazine-8-methanol

Into a solution of 40 g of lithium aluminum lithium hydride intetrahydrofuran (1 l) was dropped a solution of 200 g of methyl10H-pyrazino[2,3-b][1,4]benzothiazine-8-carboxylate in tetrahydrofuran(2.5 l) while maintaining the mixture at a temperature not exceeding 15°C. After continuing the reaction at 15° C. or below for 1 hour, 40 ml ofwater, 40 ml of a 15% aqueous solution of sodium hydroxide and 120 ml ofwater were successively added and the resulting mixture was stirred foran additional 1 hour. After filtering off the insoluble matter, thesolvent was distilled off under reduced pressure to thereby give 125 gof the title compound as yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm; 4.30(d, J=6.0 Hz, 2H), 5.17(t, J=6.0 Hz, 1H),6.70(d, J=7.9 Hz, 1H), 6.75(s, 1H), 6.83(d, J=7.9 Hz, 1H), 7.61(d, J=2.6Hz, 1H), 7.63(d, J=2.6 Hz, 1H), 9.50(s, 1H)

m.p.: 187-189° C.

MS: FAB(+)231(M⁺)

Example 4 8-Chloromethyl-10H-pyrazino[2,3-b][1,4]benzothiazine

Into a solution of 7 g of10H-pyrazino[2,3-b][1,4]benzothiazine-8-methanol and 6.1 ml of pyridinein N,N-dimethylformamide (50 ml) was added dropwise 5.9 ml ofmethanesulfonyl chloride at 0° C. After stirring at room temperature for1 hour, the reaction mixture was poured into a pre-cooled aqueoussolution of methylene chloride/sodium hydrogencarbonate, extracted withethyl acetate, washed with water and dried over anhydrous sodiumsulfate. After distilling off the solvent under reduced pressure, thecrystals thus precipitated were diluted with a small amount of ethylacetate, taken up by filtration and washed with diethyl ether. Thus 4.7g of the title compound was obtained as a yellow powder.

¹H-NMR(DMSO-d₆) δ ppm; 4.58(s, 2H), 6.78-6.80(m, 1H), 6.80-6.84(m, H),6.90(dd, J=1.7, 7.9 Hz, 1H), 7.63-7.66(m, 2H), 9.58(s, 1H)

m.p.: 161-162° C.

MS: FAB(+)249(M⁺)

Example 5 Methyl10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine-8-carboxylate

415 g of methyl 10H-pyrazino[2,3-b][1,4]benzothiazine-8-carboxylate wassuspended in 2.5 l of N,N-dimethylformamide in a nitrogen atmosphere.Then 66 g of sodium hydride (oily: 60% or more) was added in portionsthereto while maintaining the mixture at −10 to 0° C. Then the resultingmixture was stirred for 1 hour. Next, 110 g of chloromethyl methyl etherwas dropped thereinto while maintaining the mixture at a temperature notexceeding 5° C. After the completion of the reaction, the reactionmixture was poured into ice, extracted with methylene chloride twice,washed with water and dried over anhydrous sodium sulfate. Afterdistilling off the solvent under reduced pressure, diisopropyl ether wasadded to the residues and the crystals thus precipitated were taken upby filtration to thereby give 335 g of the title compound as yellowcrystals.

¹H-NMR(CDCl₃) δ ppm; 3.55(s, 3H), 3.91(s, 3H), 5.30(s, 2H), 7.55(d,J=8.5 Hz, 1H), 7.61(d, J=8.5 Hz, 1H), 7.74(s, 1H), 7.85(s, 2H)

m.p.: 151-152° C.

MS: FAB(+)303(M⁺)

Example 610-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine-8-methanol

Into a solution of 350 g of methyl10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine-8-carboxylate inmethylene chloride (2.5 l) was added dropwise under a nitrogenatmosphere 3.2 l of a 1.01 M solution of diisobutylaluminum hydride intoluene while maintaining the system at a temperature not exceeding 15°C. Then the reaction mixture was poured into ice and stirred for 1 hour.After filtering off the insoluble matter, the filtrate was washed withwater. After distilling off the solvent under reduced pressure, thecrude crystals thus obtained were washed with diisopropyl ether tothereby give 250 g of the title compound as pale yellow crystals.

¹H-NMR(CDCl₃) δ ppm; 3.53(s, 3H), 4.63(s, 2H), 5.29(s, 2H), 6.97(dd,J=1.3, 7.9 Hz, 1H), 7.01(d, J=7.9 Hz, 1H), 7.15(d, J=1.3 Hz, 1H),7.84(d, J=2.9 Hz, 1H), 7.85(d, J=2.9 Hz, 1H)

Example 78-Chloromethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine

Into a solution of 19 g of10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine-8-methanol and13.9 ml of pyridine in N,N-dimethylformamide (150 ml) was added dropwiseunder a nitrogen atmosphere 13.3 ml of methanesulfonyl chloride at 0° C.Then the reaction mixture was stirred at room temperature for 1 hour andthen poured into a pre-cooled aqueous solution of methylenechloride/sodium hydrogen carbonate. Then it was extracted with ethylacetate, washed with water and dried over anhydrous sodium sulfate.After distilling off the solvent under reduced pressure, the residue waspurified by silica gel column chromatography (eluted with methylenechloride) to thereby give 13.6 g of the title compound as pale yellowcrystals.

¹H-NMR(CDCl₃) δ ppm; 3.55(s, 3H), 4.52(s, 2H), 5.29(s, 2H), 6.99(d,J=7.6 Hz, 1H), 7.00(d, J=7.6 Hz, 1H), 7.16(s, 1H), 7.84(d, J=2.9 Hz,1H), 7.85(d, J=2.9 Hz, 1H)

m.p. 125-126° C.

MS: FAB(+)293(M⁺)

Example 8 8-Chloromethyl-10H-pyrazino[2,3-b][1,4]benzothiazine

6 g of8-chloromethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazinewas dissolved in 50 ml of tetrahydrofuran and 20 ml of 6 N hydrochloricacid was added thereto at 0° C. After stirring at room temperature for30 minutes, the reaction mixture was poured into ice-water and extractedwith ethyl acetate. The extract was washed with water, dried overanhydrous magnesium sulfate, filtered and concentrated under reducedpressure. The crystals precipitating in the course of the concentrationwere taken up by filtration and washed with diethyl ether to therebygive 4.8 g of the title compound as yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm; 4.58(s, 2H), 6.78-6.80(m, 1H), 6.80-6.84(m, 1H),6.90(dd, J=1.7, 7.9 Hz, 1H), 7.63-7.66(m, 2H), 9.58(s, 1H)

m.p.: 161-162° C.

MS: FAB(+)249(M⁺)

Example 9 8-Chloromethyl-10H-pyrazino[2,3-b][1,4]benzothiazine

Into 250 ml of a solution of 26.9 g of8-chloromethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine inmethylene chloride was dropped 50 ml of trifluoroacetic acid at 0° C.After reacting at room temperature for 12 hours, the reaction mixturewas cooled to 0° C. and neutralized by adding an aqueous solution ofsodium hydrogencarbonate. The crystals thus precipitated were taken upby filtration and washed successively with water and diethyl ether tothereby give 19.1 g of the title compound as yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm; 4.58(s, 2H), 6.78-6.80(m, 1H), 6.80-6.84(m, 1H),6.90(dd, J=1.7, 7.9 Hz, 1H), 7.63-7.66(m, 2H), 9.58(s, 1H)

m.p.: 161-162° C.

MS: FAB(+)249(M⁺)

Example 10 Methyl (syn)-(3-methyl-3-azabicyclo[3.3.1]non-9-yl)acetateoxalate

37.13 g of ethyl (3-methyl-3-azabicyclo[3.3.1]non-9-ylidene)acetate wasdissolved in 815 ml of methanol. After adding 20.24 g of magnesium, theresulting mixture was stirred at room temperature for 18 hours. Then asaturated aqueous solution of ammonium chloride was added to thereaction mixture followed by extraction with ethyl acetate. The ethylacetate layer was washed successively with water and a saturated aqueoussolution of sodium chloride and dried over anhydrous magnesium sulfate.After concentrating the solvent under reduced pressure, 34.32 g of crudemethyl (3-methyl-3-azabicyclo[3.3.1]non-9-yl)acetate was obtained.

34.32 g of this oily substance was dissolved in 343 ml of ethanol. Afteradding 19.58 g of oxalic acid dehydrate, the resulting mixture wasallowed to stand at room temperature. The crystals thus precipitatedwere recrystallized from 550 ml of ethanol to thereby give 17.76 g ofthe title compound as white needles.

¹H-NMR(DMSO-d₆) δ ppm; 1.51(m, 1H), 1.64-1.75(m, 2H), 1.78-1.86(m, 4H),1.96(m, 1H), 2.07(m, 1H), 2.60(d, J=8.6 Hz, 2H), 2.61(s, 3H),2.88-2.96(m, 2H), 3.16-3.24(m, 2H), 3.61(s, 3H)

m.p.: 181-185° C. (decomp.)

Example 11 Ethyl (syn)-(3-methyl-3-azabicyclo[3.3.1]non-9-yl)acetate

67.36 g of methyl (syn)-(3-methyl-3-azabicyclo[3.3.1]non-9-yl)acetateoxalate was dissolved in water and the solution made basic by addingaqueous ammonia. Then it was extracted with ethyl acetate. The ethylacetate layer was washed successively with water and a saturated aqueoussolution of sodium chloride and dried over anhydrous magnesium sulfate.After concentrating the solvent under reduced pressure, 46.64 g of crudemethyl (syn)-(3-methyl-3-azabicyclo[3.3.1]non-9-yl)acetate was obtained.

46.64 g of this oily substance was dissolved in 500 ml of ethanol. Afteradding 100 ml of 4 N hydrogen chloride/dioxane, the resulting mixturewas heated under reflux for 8 hours. Then the reaction mixture wasconcentrated under reduced pressure. After adding water, the residue wasmade basic by adding aqueous ammonia and then extracted with ethylacetate. The ethyl acetate layer was washed with water and a saturatedaqueous solution of sodium chloride and dried over anhydrous magnesiumsulfate. After concentrating the solvent under reduced pressure, 45.50 gof the title compound was obtained as a slightly yellow oily substance.

¹H-NMR(CDCl₃) δ ppm; 1.26(t, J=7.1 Hz, 3H), 1.46(m, 1H), 1.55-1.76(m,4H), 1.78-1.88(m, 2H), 2.00(m, 1H), 2.13(s, 3H), 2.32-2.38(m, 2H),2.41(d, J=7.9 Hz, 2H), 2.46(m, 1H), 2.57-2.65(m, 2H), 4.12(q, J=7.1 Hz,2H)

Example 12 Ethyl(syn)-[3-(vinyloxycarbonyl)-3-azabicyclo[3.3.1]non-9-yl]acetate

45.50 g of ethyl (syn)-(3-methyl-3-azabicyclo[3.3.1]non-9-yl)acetate wasdissolved in 155 ml of 1,2-dichloroethane. After adding 51.6 ml of vinylchloroformate, the resulting mixture was stirred at room temperature for45 minutes and then heated under reflux for 4 hours. Next, the reactionmixture was concentrated under reduced pressure and the residue waspurified by silica gel column chromatography (eluted with toluene/ethylacetate) to thereby give 37.63 g of the title compound as a slightlyyellow oily substance.

¹H-NMR(CDCl₃) δ ppm; 1.26(t, J=7.1 Hz, 3H), 1.52(m, 1H), 1.66-1.82(m,5H), 1.84-1.93(m, 2H), 2.16(m, 1H), 2.46(d, J=7.9 Hz, 2H), 3.23(m, 1H),3.33(m, 1H), 3.88-3.96(m, 2H), 4.15(q, J=7.1 Hz, 2H), 4.45(dd, J=1.6,6.3 Hz, 1H), 4.79(dd, J=1.6, 13.9 Hz, 1H), 7.25(dd, J=6.3, 13.9 Hz, 1H)

Example 13 Ethyl (syn)-(3-azabicyclo[3.3.1]non-9-yl)acetate

To 37.63 g of ethyl(syn)-[3-(vinyloxycarbonyl)-3-azabicyclo[3.3.1]non-9-yl]acetate wasadded 150 ml of 4 N-hydrogen chloride/dioxane and the resulting mixturewas stirred at room temperature for 1 hour. After adding 300 ml ofethanol, the reaction mixture was heated under reflux for 30 minutes.Then the reaction mixture was concentrated under reduced pressure andthe residue was made basic by adding ice-water and aqueous ammoniafollowed by extraction with methylene chloride. After drying overanhydrous sodium sulfate, the residue was concentrated under reducedpressure to thereby give 27.34 g of the title compound as a pale yellowoily substance.

¹H-NMR(CDCl₃) δ ppm; 1.26(t, J=7.1 Hz, 3H), 1.54(br.s, 2H), 1.67(m, 1H),1.76-1.94(m, 4H), 2.10-2.34(m, 3H), 2.55(d, J=7.9 Hz, 2H), 2.81-2.89(m,2H), 3.14-3.24(m, 2H), 4.13(q, J=7.1 Hz, 2H)

Example 14 Ethyl(syn)-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo-[3.3.1]non-9-yl]acetate

To 300 ml of N,N-dimethylformamide were added 30.79 g of8-chloromethyl-10H-pyrazino[2,3-b][1,4]-benzothiazine, 27.34 g of ethyl(syn)-(3-azabicyclo[3.3.1]non-9-yl)acetate and 23.65 ml ofdiisopropylethylamine and the resulting mixture was stirred at 80° C.for 3 hours. Then the reaction mixture was poured into ice/water andextracted with ethyl acetate. The ethyl acetate layer was washed withwater and a saturated aqueous solution of sodium chloride, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (eluted withtoluene/ethyl acetate). Next, it was dissolved in 1 l of ethyl acetateand extracted with 1 N hydrochloric acid. The aqueous layer was madebasic with aqueous ammonia and extracted with ethyl acetate. The ethylacetate layer was washed with water and a saturated aqueous solution ofsodium chloride, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. After adding n-hexane, the crystals thusprecipitated were taken up by filtration and washed with diisopropylether to thereby give 36.99 g of the title compound as a yellow powder.

¹H-NMR(CDCl₃) δ ppm; 1.25(t, J=7.1 Hz, 3H), 1.55(m, 1H), 1.60-1.86(m,6H), 2.00-2.08(m, 1H), 2.36-2.47(m, 4H), 2.53-2.68(m, 3H), 3.23(s, 2H),4.12(q, J=7.1 Hz, 2H), 6.41(br.s, 1H), 6.49(d, J=1.3 Hz, 1H), 6.76(dd,J=1.3, 8.1 Hz, 1H), 6.83(d, J=8.1 Hz, 1H), 7.57(d, J=2.9 Hz, 1H),7.69(d, J=2.9 Hz, 1H)

m.p.: 114-116° C.

Example 15(syn)-[3-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]non-9-yl]aceticacid

36.00 g of ethyl(syn)-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]non-9-yl]acetatewas dissolved in tetrahydrofuran (380 ml) and ethanol (380 ml). Afteradding 187 ml of 1 N sodium hydroxide, the resulting mixture was stirredat room temperature for 15 hours. Then the reaction mixture wasconcentrated under reduced pressure. After adding 200 ml of water, theresidue was concentrated under reduced pressure to thereby reduce thevolume by half. After adding 500 ml of water, it was acidified (about pH5) by adding a solution of sodium dihydrogenphosphate. After adding 800ml of ethyl acetate and stirring, the crystals thus precipitated weretaken up by filtration, washed with water and dried at 50° C. to therebygive 31.2 g of the title compound as a yellow powder.

¹H-NMR(DMSO-d₆) δ ppm; 1.46(m, 1H), 1.56-1.69(m, 4H), 1.73-1.82(m, 2H),1.89(m, 1H), 2.30-2.37(m, 4H), 2.53-2.70(m, 3H), 3.18(s, 2H), 6.69(dd,J=1.5, 7.9 Hz, 1H), 6.73(d, J=1.5 Hz, 1H), 6.84(d, J=7.9 Hz, 1H),7.63(d, J=2.7 Hz, 1H), 7.64(d, J=2.7 Hz, 1H), 9.57(s, 1H)

m.p.: 235-239° C.

MS: FAB(+)397(MH⁺)

Example 16 Ethyl (anti)-(3-methyl-3-azabicyclo[3.3.1]non-9-yl)acetate

70 g of ethyl (3-methyl-3-azabicyclo[3.3.1]non-9-ylidene)acetate wasdissolved in 700 ml of ethanol. After adding 42 ml of conc. Hydrochloricacid and 21 g of 10% palladium-carbon (moisture content: 50%), themixture was hydrogenated for 12 hours under atmospheric pressure atordinary temperature. After filtering off the palladium-carbon, thefiltrate was concentrated under reduced pressure. Next the residue wasmade basic by adding an aqueous solution of sodium hydroxide and wasextracted with ethyl acetate. The extract was washed with a saturatedaqueous solution of sodium chloride and dried over anhydrous magnesiumsulfate. After filtering, the solvent was distilled off under reducedpressure to thereby give 65 g of the title compound as a colorless oilysubstance.

¹H-NMR(CDCl₃) δ ppm; 1.25(t, J=7 Hz, 3H), 1.30-1.50(m, 1H), 1.40-1.70(m,2H), 1.63(br.s, 2H), 1.60-1.93(m, 2H), 1.90-2.05(m, 1H), 2.13(s, 3H)2.23(br.d, J=10 Hz, 2H), 2.30-2.58(m, 1H), 2.48(d, J=8 Hz, 2H),2.88(br.d, J=10 Hz, 2H), 4.13(q, J=7 Hz, 2H)

Example 17 Ethyl(anti)-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]non-9-yl]acetate

61 g of ethyl (anti)-(3-methyl-3-azabicyclo[3.3.1]non-9-yl)acetate wascooled to 0° C. and 85.2 g of 1-chloroethyl chloroformate was addeddropwise thereinto. After stirring at the same temperature for 15minutes, the reaction mixture was reacted at 100° C. for 1 hour. Then itwas brought back to room temperature and the 1-chloroethyl chloroformatewas distilled off under reduced pressure. After adding 500 ml ofethanol, the residue was heated under reflux for 1 hour. Afterdistilling off the solvent under reduced pressure, 71 g of crude ethyl(anti)-(3-azabicyclo[3.3.1]non-9-yl)acetate hydrochloride was obtained.

To 500 ml of a solution of this crude product in N,N-dimethylformamidewere added 52 g of 8-chloromethyl-10H-pyrazino[2,3-b][1,4]benzothiazineand 115 g of anhydrous potassium carbonate and the resulting mixture wasreacted at 100° C. for 4 hours and 30 minutes. Then the reaction mixturewas cooled to 0° C., added to a mixture of ice/water with ethyl acetateand extracted with ethyl acetate. The extract was washed with asaturated aqueous solution of sodium chloride and dried over anhydrousmagnesium sulfate. After distilling off the solvent under reducedpressure, the obtained residue was purified by silica gel columnchromatography (eluted with methylene chloride/ethyl acetate) to therebygive 51 g of the title compound as a yellow powder.

¹H-NMR(DMSO-d₆) δ ppm; 1.14(t, J=7 Hz, 3H), 1.34-1.48(m, 3H), 1.56(br.s,2H), 1.60-1.75(m, 2H), 1.82-1.92(m, 1H), 2.15(br.d, J=11 Hz, 2H),2.43(d, J=8 Hz, 2H), 2.4-2.6(m, 1H), 2.85(br.d, J=9 Hz, 2H), 3.15(s,2H), 4.02(q, J=7 Hz, 2H), 6.67(dd, J=2, 8 Hz, 1H), 6.71(d, J=2 Hz, 1H),6.82(d, J=8 Hz, 1H), 7.61(d, J=3 Hz, 1H), 7.62(d, J=3 Hz, 1H), 9.55(s,1H)

m.p.: 142-143° C.

MS: FAB(+)425(MH⁺)

Example 18(anti)-[3-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]non-9-yl]aceticacid

31 g of ethyl(anti)-[3-(10H-pyrazino[2,3-b][1,4)benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]non-9-yl]acetatewas dissolved in ethanol (150 ml) and tetrahydrofuran (150 ml). Afteradding 75 ml of an aqueous solution of 8.8 g of sodium hydroxide, theresulting mixture was heated under reflux in a nitrogen atmosphere for 1hour. Then the reaction mixture was washed with a saturated aqueoussolution of sodium chloride, dried over anhydrous magnesium sulfate andfiltered. After distilling off the solvent under reduced pressure, thecrystals precipitated in the course of the distillation were taken up byfiltration to thereby give 18.6 g of the title compound as a yellowpowder.

¹H-NMR(DMSO-d₆) δ ppm; 1.34-1.48(m, 3H), 1.58(br.s, 2H), 1.60-1.76(m,2H), 1.80-1.90(m, 1H), 2.14(br.d, J=10 Hz, 2H), 2.33(d, J=8 Hz, 2H),2.44-2.60(m, 1H), 2.85(br.d, J=10 Hz, 2H), 3.15(s, 2H), 6.67(d, J=8 Hz,1H), 6.72(s, 1H), 6.82(d, J=8 Hz, 1H), 7.60(d, J=3 Hz, 1H), 7.62(d, J=3Hz, 1H), 9.54(s, 1H)

m.p.: 215-217° C.

MS: FAB(+)397(MH⁺)

Example 19 Ethyl(±)-(6R*,7R*)-(3,6,7-trimethyl-3-azabicyclo[3.2.1]oct-8-ylidene)acetate

To a solution of 8 g of paraformaldehyde in methanol (100 ml) were added10 ml of a 40% solution of methylamine in methanol, 7.7 ml of aceticacid and 10 g of 3,4-dimethylcyclopentanone and the resulting mixturewas heated under reflux for 1.5 hours. After distilling off the solventunder reduced pressure, the residue was acidified by adding a diluteaqueous solution of hydrochloric acid and then was extracted with ethylacetate. The aqueous layer was made basic with a dilute aqueous solutionof sodium hydroxide and then extracted with ethyl acetate. The organiclayer was dried over anhydrous magnesium sulfate and the solvent wasdistilled off under reduced pressure. Then the obtained residue wasdistilled under reduced pressure (70-75° C./1 mmHg) to thereby give 2.7g of crude (6R*,7R*)-3,6,7-trimethyl-3-azabicyclo[3.2.1]octan-8-one as apale yellow oily substance.

To a solution of 4.35 g of triethyl phosphonoacetate in tetrahydrofuran(50 ml) was added 0.85 g of sodium hydride (oily: 60-72%) underice-cooling and the resulting mixture was stirred at 0° C. for 10minutes. Then a solution of 2.7 g of the crude(6R*,7R*)-3,6,7-trimethyl-3-azabicyclo[3.2.1]octan-8-one intetrahydrofuran (20 ml) was added thereto and the reaction mixture washeated under reflux for 1 hour. After adding ethyl acetate, the reactionmixture was washed with a saturated aqueous solution of sodium chlorideand the organic layer was dried over anhydrous magnesium sulfate. Afterdistilling off the solvent under reduced pressure, the residue waspurified by silica gel column chromatography (eluted with n-hexane/ethylacetate) to thereby give 1.6 g of the title compound as a pale yellowoily substance.

¹H-NMR(CDCl₃) δ ppm; 0.90(d, J=7.2 Hz, 3H), 1.17(d, J=7.2 Hz, 3H),1.29(t, J=7.2 Hz, 3H), 1.40-1.50(m, 1H), 1.74-1.93(m, 1H), 2.08-2.30(m,3H), 2.20(s, 3H), 2.80-2.90(m, 1H), 2.90-3.00(m, 1H), 3.35-3.44,3.50-3.58(m, total 1H), 4.15(q, J=7.2 Hz, 2H), 5.58, 5.66(s, total 1H)

Example 20 Ethyl(±)-(anti)-(6R*,7R*)-(3,6,7-trimethyl-3-azabicyclo[3.2.1]oct-8-yl)acetate

To a solution of 1.6 g of ethyl(6R*,7R*)-(3,6,7-trimethyl-3-azabicyclo[3.2.1]oct-8-ylidene)acetate inmethanol (100 ml) was added 0.4 g of 10% palladium-carbon (moisturecontent: 50%) and the resulting mixture was stirred under a hydrogen gasstream at room temperature overnight. Then the reaction mixture wasfiltered through celite. After distilling off the solvent under reducedpressure, 1.6 g of the title compound was obtained as a pale yellow oilysubstance.

¹H-NMR(CDCl₃) δ ppm; 1.06(d, J=7.2 Hz, 3H), 1.08(d, J=7.2 Hz, 3H),1.26(t, J=6.4 Hz, 3H), 1.63-1.84(m, 4H), 1.92(t, J=8.0 Hz, 1H), 2.02(d,J=9.6 Hz, 1H), 2.08(d, J=9.6 Hz, 1H), 2.21(s, 3H), 2.37(d, J=8.0 Hz,2H), 2.67(d, J=9.6 Hz, 1H), 2.85(d, J=9.6 Hz, 1H), 4.13(q, J=6.4 Hz, 2H)

Example 21 Ethyl(±)-(anti)-(6R*,7R*)-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-6,7-dimethyl-3-azabicyclo[3.2.1]oct-8-yl]acetate

To a solution of 1.6 g of ethyl(anti)-(6R*,7R*)-(3,6,7-trimethyl-3-azabicyclo[3.2.1]oct-8-yl)acetate in1,2-dichloroethane (70 ml) was added 2.2 ml of 1-chloroethylchloroformate and the resulting mixture was heated under reflux for 1.5hours. After distilling off the solvent under reduced pressure, 500 mlof methanol was added to the residue and the mixture was heated underreflux for 1 hour. After distilling off the solvent under reducedpressure, a dilute aqueous solution of sodium hydroxide was added to theresidue followed by the extraction with ethyl acetate. The organic layerwas dried over anhydrous magnesium sulfate and then the solvent wasdistilled off under reduced pressure. To a solution of the residue inN,N-dimethylformamide (50 ml) were added 1.1 g of8-chloromethyl-10H-pyrazino[2,3-b][1,4]benzothiazine and 1.9 g ofpotassium carbonate and the resulting mixture was stirred for 2 hours at100° C. After adding ethyl acetate, the reaction mixture was washed witha saturated aqueous solution of sodium chloride thrice and then theorganic layer was dried over anhydrous magnesium sulfate. Afterdistilling off the solvent under reduced pressure, the residue waspurified by silica gel column chromatography (eluted with methylenechloride/methanol) to thereby give 2.0 g of the title compound as ayellow oily substance.

¹H-NMR(CDCl₃) δ ppm; 1.06(d, J=7.2 Hz, 3H), 1.09(d, J=7.2 Hz, 3H),1.25(t, J=7.2 Hz, 3H), 1.60-1.82(m, 4H), 1.96(t, J=8.0 Hz, 1H), 2.05(d,J=9.2 Hz, 1H), 2.13(d, J=9.2 Hz, 1H), 2.37(d, J=7.2 Hz, 2H), 2.64(dd,J=3.6, 9.2 Hz, 1H), 2.84(dd, J=3.6, 9.2 Hz, 1H), 3.24(d, J=13.2 Hz, 1H),3.36(d, J=13.2 Hz, 1H), 4.13(q, J=7.2 Hz, 2H), 6.49(d, J=1.6 Hz, 1H),6.52(s, 1H), 6.76(dd, J=1.6, 8.0 Hz, 1H), 6.81(d, J=8.0 Hz, 1H), 7.57(d,J=2.8 Hz, 1H), 7.69(d, J=2.8 Hz, 1H)

Example 22 Ethyl(+)-(anti)-(6R*,7R*)-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-6,7-dimethyl-3-azabicyclo[3.2.1]oct-8-yl]acetateand ethyl(−)-(anti)-(6R*,7R*)-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-6,7-dimethyl-3-azabicyclo[3.2.1]oct-8-yl]acetate

0.2 g of ethyl(±)-(anti)-(6R*,7R*)-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-6,7-dimethyl-3-azabicyclo-[3.2.1]oct-8-yl]acetatewas dissolved in ethanol (5 ml) and n-hexane (5 ml) and the enantiomerswere resolved by using CHIRALPAK AD [20 (diameter)×250 mm; mfd. byDaicel Chemical Industries, Ltd.; eluted with ethanol at 10 ml/min].Thus the (+)-compound was eluted first followed by the (−)-compound.From 1.4 g of the racemic modification, 0.59 g (99% e.e. or above) and0.52 g (98.7% e.e.) of the (+)- and (−)-compounds were obtainedrespectively each as a yellow oily substance.

(+)-compound: α²⁵ _(D)+20.6° (c=1.02 THF)

(−)-compound: α²⁵ _(D)−19.7° (c=1.01 THF)

Example 23(+)-(anti)-(6R*,7R*)-[3-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-6,7-dimethyl-3-azabicyclo[3.2.1]oct-8-yl]aceticacid

To a solution of 0.575 g of ethyl(+)-(anti)-(6R*,7R*)-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-6,7-dimethyl-3-azabicyclo[3.2.1]oct-8-yl]acetatein a solvent. mixture of tetrahydrofuran (10 ml) with methanol (10 ml)was added 2 ml of a 4 N aqueous solution of sodium hydroxide and theresulting mixture was stirred at 60° C. for 50 minutes. After furtheradding 1 ml of a 4 N aqueous solution of sodium hydroxide, the resultingmixture was reacted at the same temperature for 30 minutes. After thecompletion of the reaction, the solvent was distilled off under reducedpressure and the residue was suspended in water. The pH value thereofwas regulated to 5 with a 1 N aqueous solution of hydrochloric acid thenthe mixture was extracted with ethyl acetate. The extract was dried overanhydrous magnesium sulfate and concentrated under reduced pressure.Then the residue was purified by silica gel column chromatography(eluted with methylene chloride/methanol) to thereby give 0.49 g of thetitle compound as yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm; 1.01(d, J=7.2 Hz, 3H), 1.05(d, J=7.2 Hz, 3H),1.60-1.80(m, 4H), 1.83(t, J=7.2 Hz, 1H), 1.97(d, J=10 Hz, 1H), 2.04(d,J=10 Hz, 1H), 2.27(d, J=7.6 Hz, 2H), 2.59(dd, J=4.0, 10 Hz, 1H),2.78(dd, J=2.8, 10 Hz, 1H), 3.21(d, J=13.2 Hz, 1H), 3.30(d, J=13.2 Hz,1H), 6.70(d, J=8.0 Hz, 1H), 6.74(br.s, 1H), 6.84(d, J=8.0 Hz, 1H),7.63(d, J=2.8 Hz, 1H), 7.65(d, J=2.8 Hz, 1H), 9.55(s, 1H)

α²⁵ _(D)+21.2° (c=1.03 THF)

m.p.: 179-180° C.

MS: FAB(+)411(MH⁺)

Example 24(−)-(anti)-(6R*,7R*)-[3-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-6,7-dimethyl-3-azabicyclo[3.2.1]oct-8-yl]aceticacid

0.277 g of the title compound was obtained as yellow crystals bytreating 0.509 g of ethyl(−)-(anti)-(6R*,7R*)-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-6,7-dimethyl-3-azabicyclo[3.2.1]oct-8-yl]acetatein the same manner as described in Example 23.

¹H-NMR(DMSO-d₆) δ ppm; 1.01(d, J=7.2 Hz, 3H), 1.05(d, J=7.2 Hz, 3H),1.60-1.80(m, 4H), 1.83(t, J=7.2 Hz, 1H), 1.97(d, J=10 Hz, 1H), 2.04(d,J=10 Hz, 1H), 2.27(d, J=7.6 Hz, 2H), 2.59(dd, J=4.0, 10 Hz, 1H),2.78(dd, J=2.8, 10 Hz, 1H), 3.21(d, J=13.2 Hz, 1H), 3.30(d, J=13.2 Hz,1H), 6.70(d, J=8.0 Hz, 1H), 6.74(br.s, 1H), 6.84(d, J=8.0 Hz, 1H),7.63(d, J=2.8 Hz, 1H), 7.65(d, J=2.8 Hz, 1H), 9.55(s, 1H)

α²⁵ _(D)−21.3° (c=1.01 THF)

m.p.: 179-180° C.

MS: FAB(+)411(MH⁺)

Example 25 Ethyl(±)-(6R*,8R*)-(3,6,8-trimethyl-3-azabicyclo[3.3.1]non-9-ylidene)acetate

To a solution of 180 g of paraformaldehyde in methanol (500 ml) wereslowly added under ice-cooling 230 ml of a 40% solution of methylaminein methanol and 17 ml of acetic acid. After adding dropwise a solutionof 250 ml of 3,5-dimethylcyclohexanone in methanol (1 l) thereinto, theresulting mixture was heated under reflux for 5 hours. Then the reactionmixture was cooled to room temperature and the solvent was distilled offunder reduced pressure. The residue was acidified by adding dilutehydrochloric acid and then extracted with ethyl acetate. The aqueouslayer was made basic by adding sodium hydroxide and then extracted withethyl acetate. The organic layer was dried over anhydrous magnesiumsulfate and the solvent was distilled off under reduced pressure. Thenthe residue was distilled under reduced pressure (100-110° C./1 mmHg) tothereby give 79 g of crude(6R*,8R*)-3,6,8-trimethyl-3-azabicyclo[3.3.1]nonan-9-one as a paleyellow oily substance.

To a solution of 130 g of triethyl phosphono acetate in tetrahydrofuran(600 ml) was added 25 g of sodium hydride (oily: 60% or above) underice-cooling and the resulting mixture was stirred at room temperaturefor 10 minutes. Then a solution of 70 g of the crude(6R*,8R*)-3,6,8-trimethyl-3-azabicyclo[3.3.1]nonan-9-one intetrahydrofuran (300 ml) was added thereto and the reaction mixture washeated under reflux for 2 hours. After adding ethyl acetate, thereaction mixture was washed twice with a saturated aqueous solution ofsodium chloride and the organic layer was dried over anhydrous magnesiumsulfate. After distilling off the solvent under reduced pressure, theresidue was purified by silica gel column chromatography (eluted withn-hexane/ethyl acetate) to thereby give 31.5 g of the title compound asa pale yellow oily substance.

¹H-NMR(CDCl₃) δ ppm; 0.80-1.00(m, 1H), 0.96(d, J=6.8 Hz, 3H), 1.02(d,J=6.8 Hz, 3H), 1.28(t, J=6.8 Hz, 3H), 1.70-1.77(m, 1H), 1.81-1.86(m,1H), 2.00-2.12(m, 4H), 2.20(s, 3H), 2.75(m, 2H), 3.58-3.62(m, 1H),4.16(q, J=6.8 Hz, 2H), 5.66(s, 1H)

Example 26 Ethyl(±)-(anti)-(6R*,8R*)-(3,6,8-trimethyl-3-azabicyclo[3.3.1]non-9-yl)acetate

To a solution of 31.5 g of ethyl(±)-(6R*,8R*)-(3,6,8-trimethyl-3-azabicyclo[3.3.1]non-9-ylidene)acetatein methanol (300 ml) was added 6 g of 10% palladium-carbon (moisturecontent: 50%) and the resulting mixture was stirred at room temperaturefor 12 hours under a hydrogen gas stream. Then the reaction mixture wasfiltered through celite and the solvent was distilled off under reducedpressure. Thus 30.7 g of the title compound was obtained as a paleyellow oily substance.

¹H-NMR(CDCl₃) δ ppm; 0.80-1.00(m, 1H), 1.02(d, J=6.8 Hz, 6H), 1.28(t,J=6.8 Hz, 3H), 1.38-1.48(m, 2H), 1.70-1.90(m, 2H), 1.92-2.08(m, 2H),2.10-2.15(m, 2H), 2.22(s, 3H), 2.45(d, J=6.8 Hz, 2H), 2.56-2.70(m, 2H),4.41(q, J=6.8 Hz, 2H)

Example 27 Ethyl(±)-(anti)-(6R*,8R*)-2-(3,6,8-trimethyl-3-azabicyclo[3.3.1]non-9-yl)propanoate

To a solution of 6 g of diisopropylamine in tetrahydrofuran (60 ml) wasadded 33 ml of a 1.6 M solution of n-butyl]ithium in hexane at −70° C.and the resulting mixture was stirred at 0° C. for 30 minutes. Afterrecooling to −70° C., a solution of 10.1 g of ethyl(anti)-(6R*,8R*)-2-(3,6,8-trimethyl-3-azabicyclo[3.3.1]non-9-yl)acetatein tetrahydrofuran (40 ml) was added dropwise thereinto and theresulting mixture was stirred at −70° C. for 2 hours. Then 3 ml ofmethyl iodide was added dropwise into the reaction mixture and themixture was stirred at −70° C. for 2 hours. After adding a saturatedaqueous solution of ammonium chloride, the mixture was extracted withethyl acetate twice. The organic layer was dried over anhydrousmagnesium sulfate and the solvent was distilled off under reducedpressure. Thus 11.2 g of the title compound was obtained as a paleyellow oily substance.

¹H-NMR(CDCl₃) δ ppm; 0.80-1.00(m, 1H), 1.00(d, J=6.8 Hz, 3H), 1.02(d,J=6.8 Hz, 3H), 1.18(d, J=6.8 Hz, 3H), 1.30(t, J=6.8 Hz, 3H),1.30-1.40(m, 2H), 1.70-1.85(m, 2H), 1.90-2.00(m, 2H), 2.05-2.16(m, 2H),2.20(s, 3H), 2.52-2.78(m, 3H), 4.14(q, J=6.8 Hz, 2H)

Example 28 Ethyl(±)-(anti)-(6R*,8R*)-2-[3-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-6,8-dimethy-3-azabicyclo[3.3.1]non-9-yl)propanoate

To a solution of 18.2 g of ethyl(anti)-(6R*,8R*)-2-(3,6,8-trimethyl-3-azabicyclo[3.3.1]non-9-yl)propanoatein 1,2-dichloroethane (180 ml) was added 9 ml of 1-chloroethylchloroformate and the resulting mixture was heated under reflux for 2hours. After distilling off the solvent under reduced pressure, 200 mlof methanol was added to the residue and the mixture was heated underreflux for 1 hour. After distilling off the solvent under reducedpressure, the residue was made basic by adding a dilute aqueous solutionof sodium hydroxide and was then extracted with ethyl acetate. Theorganic layer was dried over anhydrous magnesium sulfate and then thesolvent was distilled off under reduced pressure. To a solution of theresidue in N,N-dimethylformamide (100 ml) were added 2 g of8-chloromethyl-10H-pyrazino[2,3-b][1,4]benzothiazine and 3.3 g ofpotassium carbonate and the resulting mixture was stirred at 80° C. for2 hours. After adding ethyl acetate, the reaction mixture was washedwith a saturated aqueous solution of sodium chloride thrice and then theorganic layer was dried over anhydrous magnesium sulfate. Afterdistilling off the solvent under reduced pressure, the residue waspurified by silica gel column chromatography (eluting withn-hexane/ethyl acetate) to thereby give 3 g of the title compound as ayellow oily substance.

¹H-NMR(CDCl₃) δ ppm; 0.80-1.00(m, 1H), 0.98(d, J=6.8 Hz, 3H), 1.00(d,J=6.8 Hz, 3H), 1.15(d, J=6.8 Hz, 3H), 1.26(t, J=6.8 Hz, 3H),1.30-1.37(m, 1H), 1.42-1.50(m, 1H), 1.55-1.85(m, 4H), 1.98(d, J=7.2 Hz,2H), 2.58(d, J=7.2 Hz, 1H), 2.64(d, J=7.2 Hz, 1H), 2.65-2.80(m, 1H),3.26(s, 2H), 4.14(q, J=6.8 Hz, 2H), 6.40(br.s, 1H), 6.51(s, 1H), 6.76(d,J=8.0 Hz, 1H), 6.82(d, J=8.0 Hz, 1H), 7.56(d, J=2.8 Hz, 1H), 7.68(d,J=2.8 Hz, 1H)

Example 29 Ethyl(+)-(anti)-(6R*,8R*)-2-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-6,8-dimethyl-3-azabicyclo[3.3.1]non-9-yl]propanoateand ethyl(−)-(anti)-(6R*,8R*)-2-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-6,8-dimethyl-3-azabicyclo[3.3.1]non-9-yl]propanoate

0.53 g of ethyl(+)-(anti)-(6R*,8R*)-2-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-6,8-dimethyl-3-azabicyclo[3.3.1]non-9-yl]propanoatewas dissolved in a solvent mixture of n-hexane with ethanol (97:3) andthe enantiomers were resolved by using CHIRALPAK AD [5 (diameter)×50 cm;mfd. by Daicel Chemical Industries, Ltd.; eluting with n-hexane/ethanol(97.5:2.5) at 150 ml/min]. Thus the (+)-compound was eluted firstfollowed by the (−)-compound. From 120 g of the racemic mixture, 41 g(100% e.e.) and 37 g (99% e.e. or above) of the (+)- and (−)-compoundswere obtained respectively each as yellow crystals.

(+)-compound: α²⁵ _(D) +15.0° (c = 1.00 EtOH) m.p. : 135 − 136° C. MS :FAB(+)467(MH⁺) (−)-compound: α²⁵ _(D) − 14.7° (c = 1.02 EtOH) m.p. : 135− 136° C. MS : FAB(+)467(MH⁺)

Example 30(+)-(anti)-(6R*,8R*)-2-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-6,8-dimethyl-3-azabicyclo[3.3.1]non-9-yl]propanoicacid

22.2 g of ethyl(+)-(anti)-(6R*,8R*)-2-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-6,8-dimethyl-3-azabicyclo[3.3.1]non-9-yl]propanoatewas dissolved in ethanol (530 ml) and water (130 ml). After adding 6.0 gof lithium hydroxide, the resulting mixture was heated under refluxunder a nitrogen gas stream for 24 hours. After distilling off thesolvent under reduced pressure, the residue was neutralized by adding adilute aqueous solution of hydrochloric acid and then acidified byadding an aqueous solution of sodium dihydrogenphosphate then themixture was extracted with ethyl acetate. The organic layer was driedover anhydrous magnesium sulfate and the solvent was concentrated underreduced pressure to thereby give yellow crystals. After recrystallizingfrom ethyl acetate/diisopropyl ether, 18 g of the title compound wasobtained as yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm; 0.84-1.00(m, 1H), 0.95(d, J=6.8 Hz, 3H), 0.98(d,J=6.8 Hz, 3H), 1.06(d, J=6.8 Hz, 3H), 1.28-1.38(m, 2H), 1.54-1.82(m,4H), 1.87(d, J=7.2 Hz, 1H), 1.89(d, J=7.2 Hz, 1H), 2.48-2.55(m, 1H),2.55(d, J=7.2 Hz, 1H), 2.60(d, J=7.2 Hz, 1H), 3.24(s, 2H), 6.68(d, J=8.0Hz, 1H), 6.75(s, 1H), 6.84(d, J=8.0 Hz, 1H), 7.61(d, J=2.8 Hz, 1H),7.63(d, J=2.8 Hz, 1H), 9.52(br.s, 1H), 12.0(br.s, 1H)

α²⁵ _(D)+6.31° (c=1.03, THF)

m.p.: 205-210° C.

MS: FAB(+)439(MH⁺)

Example 31(−)-(anti)-(6R*,8R*)-2-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-6,8-dimethyl-3-azabicyclo[3.3.1]non-9-yl]propanoicacid

0.3 g of the title compound was obtained as yellow crystals by treating0.5 g of ethyl(−)-(anti)-(6R*,8R*)-2-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-6,8-dimethyl-3-azabicyclo[3.3.1]non-9-yl]propanoatein the same manner as described in Example 30.

¹H-NMR(DMSO-d₆) δ ppm; 0.84-1.00(m, 1H), 0.95(d, J=6.8 Hz, 3H), 0.98(d,J=6.8 Hz, 3H), 1.06(d, J=6.8 Hz, 3H), 1.28-1.38(m, 2H), 1.54-1.82(m,4H), 1.87(d, J=7.2 Hz, 1H), 1.89(d, J=7.2 Hz, 1H), 2.48-2.55(m, 1H),2.55(d, J=7.2 Hz, 1H), 2.60(d, J=7.2 Hz, 1H), 3.24(s, 2H), 6.68(d, J=8.0Hz, 1H), 6.75(s, 1H), 6.84(d, J=8.0 Hz, 1H), 7.61(d, J=2.8 Hz, 1H),7.63(d, J=2.8 Hz, 1H), 9.52(br.s, 1H), 12.0(br.s, 1H)

α²⁵ _(D)−5.72° (c=1.03, THF)

m.p.: 205-210° C.

MS: FAB(+)439(MH⁺)

Production Example 1[(anti)-2-(6R*,8R*)-3,6,8-Trimethyl-3-azabicyclo[3.3.1]non-9-yl]ethylacetate

To a solution of 8.5 g of ethyl(anti)-(6R*,8R*)-[3,6,8-trimethyl-3-azabicyclo[3.3.1]non-9-yl]acetate intetrahydrofuran (100 ml) was slowly added 0.9 g of aluminum hydrideunder ice-cooling and the resulting mixture was stirred at 0 OC for 30minutes. Next, a mixture of methanol with water was slowly added to thereaction mixture. After being diluted with ethyl acetate, the reactionmixture was filtered through celite. After distilling off the solventunder reduced pressure, 7.6 g of a pale yellow oily substance wasobtained.

To a solution of 7.6 g of this pale yellow oily substance in methylenechloride (100 ml) were added 5.5 g of acetic anhydride, 7.5 ml oftriethylamine and 0.44 g of 4-dimethylaminopyridine and the resultingmixture was stirred at room temperature for 2.5 days. Then the reactionmixture was washed with water and the organic layer was dried overanhydrous magnesium sulfate. After distilling off the solvent underreduced pressure, the residue was purified by silica gel columnchromatography (eluting with methylene chloride/methanol) to therebygive 7.6 g of the title compound as a pale yellow oily substance.

¹H-NMR(CDCl₃) δ ppm; 0.70-1.08(m, 6H), 0.98(d, J=6.8 Hz, 3H), 1.02(d,J=6.8 Hz, 3H), 1.60-2.00(m, 5H), 2.05(s, 3H), 2.06(s, 3H), 2.60-2.70(m,2H), 4.07(t, J=6.8 Hz, 2H)

Production Example 2[(anti)-2-[(6R*,8R*)-3-(Vinyloxycarbonyl)-6,8-dimethyl-3-azabicyclo[3.3.1]non-9-yl]ethyl]acetate

To a solution of 7.6 g of[(anti)-2-[(6R*,8R*)-3,6,8-trimethyl-3-azabicyclo[3.3.1]nonan-9-yl]ethyl]acetatein 1,2-dichloroethane (100 ml) was added 3.8 ml of vinyl chloroformateand the resulting mixture was heated under reflux for 1 hour. Afterdistilling off the solvent under reduced pressure, the residue waspurified by silica gel column chromatography (eluting withn-hexane/ethyl acetate) to thereby give 5.1 g of the title compound as apale yellow oily substance.

¹H-NMR(CDCl₃) δ ppm; 0.90-1.0(m, 1H), 0.98(d, J=6.8 Hz, 3H), 1.02(d,J=6.8 Hz, 3H), 1.40-1.60(m, 4H), 1.74-1.90(m, 3H), 2.05(s, 3H),2.70-2.90(m, 2H), 3.92-4.26(m, 4H), 4.43(m, 2H), 4.78(d, J=16 Hz, 1H),7.12-7.25(m, 1H)

Production Example 3(anti)-(6R*,8R*)-[3-(Vinyloxycarbonyl)-6,8-dimethyl-3-azabicyclo[3.3.1]non-9-yl]acetaldehyde

To a solution of 5.1 g of[(anti)-2-azabicyclo[3.3.1]non-9-yl]ethyl]acetate in methanol (50 ml)was added 7 ml of a 5 N aqueous solution of sodium hydroxide and theresulting mixture was stirred at room temperature for 1 hour. Afterdistilling off the solvent under reduced pressure, the residue wasneutralized by adding dilute hydrochloric acid and then extracted withethyl acetate. The organic layer was dried over anhydrous magnesiumsulfate and the solvent was distilled off under reduced pressure tothereby give 4.3 g of(anti)-(6R*,8R*)-2-[3-(vinyloxycarbonyl)-6,8-dimethyl-3-azabicyclo[3.3.1]non-9-yl]ethanolas a yellow oily substance.

Into a solution of 3.6 g of oxalyl chloride in methylene chloride (50ml) was added dropwise 2.6 ml of dimethyl sulfoxide at −70° C. Afterstirring for 10 minutes, a solution of 2.5 g of(anti)-(6R*,8R*)-2-[3-(vinyloxycarbonyl)-6,8-dimethyl-3-azabicyclo[3.3.1]non-9-yl]ethanolin methylene chloride (30 ml) was added dropwise thereinto. Afterstirring at −70° C. for 3 hours, 7.8 ml of triethylamine was addedthereto. Then the reaction mixture was brought back to room temperatureand washed with water. The organic layer was dried over anhydrousmagnesium sulfate and the solvent was distilled off under reducedpressure. The residue was purified by silica gel column chromatography(eluting with n-hexane/ethyl acetate) to thereby give 2.1 g of the titlecompound as a pale yellow oily substance.

¹H-NMR(CDCl₃) δ ppm; 0.98(d, J=6.8 Hz, 3H), 1.02(d, J=6.8 Hz, 3H),1.42-1.70(m, 5H), 1.85-1.95(m, 1H), 2.17-2.23(m, 1H), 2.64(d, J=6.8 Hz,2H), 2.80-2.95(m, 2H), 3.94-4.08(m, 2H), 4.46(d, J=6.8 Hz, 1H), 4.78(d,J=16 Hz, 1H), 7.20(dd, J=6.8, 16 Hz, 1H), 9.72(t, J=6.8 Hz, 1H)

Production Example 4 Ethyl(anti)-[3-(vinyloxycarbonyl)-3-azabicyclo[3.3.1]non-9-yl]acetate

0.78 g of ethyl (anti)-(3-methyl-3-azabicyclo[3.3.1]non-9-yl]acetate wasdissolved in 10 ml of 1,2-dichloroethane. After adding 0.6 ml of vinylchloroformate, the resulting mixture was stirred at room temperature for1 hour and then heated under reflux for 2 hours. The reaction mixturewas concentrated and, after adding water, extracted with ethyl acetate.The ethyl acetate layer was washed with 1 N hydrochloric acid, asaturated aqueous solution of sodium hydrogencarbonate and a saturatedaqueous solution of sodium chloride and dried over anhydrous sodiumsulfate. After concentrating the solvent under reduced pressure, 0.52 gof the title compound was obtained as a pale brown oily substance.

¹H-NMR(CDCl₃) δ ppm; 1.27(t, J=7.1 Hz, 3H), 1.48(m, 1H), 1.59-1.83(m,7H), 2.21(m, 1H), 2.53(d, J=7.5 Hz, 2H), 3.15(m, 1H), 3.23(m, 1H),4.15(q, J=7.1 Hz, 2H), 4.17-4.26(m, 2H), 4.45(dd, J=1.5, 6.3 Hz, 1H),4.79(dd, J=1.5, 13.9 Hz, 1H), 7.25(dd, J=6.3, 13.9 Hz, 1H)

Production Example 5(anti)-[3-(Vinyloxycarbonyl)-3-azabicyclo[3.3.1]non-9-yl]acetic acid

3.01 g of ethyl(anti)-[3-(vinyloxycarbonyl)-3-azabicyclo[3.3.1]non-9-yl]acetate wasdissolved in 30 ml of ethanol. After adding 16.1 ml of 1 N sodiumhydroxide, the resulting mixture was stirred at room temperature for 4hours. Then the reaction mixture was concentrated and water was addedthereto. The aqueous layer was washed with ether and acidified with 1 Nhydrochloric acid and then extracted with ethyl acetate. After dryingthe extracts over anhydrous sodium sulfate and concentrating the solventunder reduced pressure, 2.9 g of the title compound was obtained as apale yellow oily substance.

¹H-NMR(CDCl₃) δ ppm; 1.50(m, 1H), 1.60-1.86(m, 7H), 2.22(m, 1H), 2.60(d,J=7.5 Hz, 2H), 3.15(m, 1H), 3.23(m, 1H), 4.17-4.28(m, 2H), 4.45(dd,J=1.6, 6.4 Hz, 1H), 4.79(dd, J=1.6, 14.1 Hz, 1H), 7.24(dd, J=6.4, 14.1Hz, 1H)

Production Example 6(anti)-2-[3-(Vinyloxycarbonyl)-3-azabicyclo[3.3.1]non-9-yl]ethanol

To a solution of 500 mg of(anti)-[3-(vinyloxycarbonyl)-3-azabicyclo[3.3.1]non-9-yl]acetic acid intetrahydrofuran (10 ml) were added 294 mg of N-hydroxysuccinimide and449 mg of N,N′-dicyclohexyl carbodiimide and the resulting mixture wasstirred at room temperature for 8 hours. Next, the reaction mixture wasice-cooled and 187 mg of sodium borohydride was added thereto. Afterstirring for 20 minutes, the reaction mixture was stirred at roomtemperature for an additional 15 hours and then was extracted with ethylacetate containing ice/water. The ethyl acetate layer was washed withwater, 1 N sodium hydroxide and a saturated aqueous solution of sodiumchloride and dried over anhydrous magnesium sulfate. After concentratingunder reduced pressure, the matters insoluble in methylene chloride werefiltered off. Then the residue was purified by silica gel columnchromatography (eluting with methylene chloride/methanol) to therebygive 348 mg of the title compound as a colorless oily substance.

¹H-NMR(CDCl₃) δ ppm; 1.41-1.90(m, 12H), 3.12(m, 1H), 3.19(m, 1H),3.73(t, J=6.4 Hz, 2H), 4.17-4.25(m, 2H), 4.44(dd, J=1.5, 6.2 Hz, 1H),4.78(dd, J=1.5, 14.1 Hz, 1H), 7.25(dd, J=6.2, 14.1 Hz, 1H)

Production Example 7(anti)-[3-(Vinyloxycarbonyl)-3-azabicyclo[3.3.1]non-9-yl]acetaldehyde

0.32 ml of oxalyl chloride was dissolved in 8 ml of methylene chloride,cooled to −60° C. and stirred. 0.28 ml of dimethyl sulfoxide wasdissolved in 1 ml of methylene chloride and then was added dropwise tothe above solution while maintaining the bulk temperature at −50° C. orbelow. 5 minutes thereafter, 580 mg of(anti)-2-[3-(vinyloxycarbonyl)-3-azabicyclo[3.3.1]non-9-yl]ethanol wasdissolved in 2 ml of methylene chloride and added dropwise to the abovemixture while maintaining the bulk temperature at −50° C. or below.After 15 minutes, 1.7 ml of triethylamine was added dropwise to whilemaintaining the bulk temperature at −50° C. or below. After 20 minutes,the reaction mixture was heated to room temperature and stirred for 1hour. After adding water, the reaction mixture was extracted with ethylacetate. The ethyl acetate layer was washed with 1 N hydrochloric acid,a saturated aqueous solution of sodium hydrogencarbonate and a saturatedaqueous solution of sodium chloride, dried over anhydrous sodium sulfateand concentrated under reduced pressure. Then the residue was purifiedby silica gel column chromatography (eluting with n-hexane/ethylacetate) to thereby give 451 mg of the title compound as a colorlessoily substance.

¹H-NMR(CDCl₃) δ ppm; 1.48(m, 1H), 1.60-1.82(m, 7H), 2.33(m, 1H),2.66-2.72(m, 2H), 3.18(m, 1H), 3.25(m, 1H), 4.08-4.13(m, 2H), 4.45(dd,J=1.6, 6.2 Hz, 1H), 4.79(dd, J=1.6, 14.0 Hz, 1H), 7.25(dd, J=6.2, 14.0Hz, 1H), 9.83(t, J=1.6 Hz, 1H)

Production Example 81-[3-[N-(2-Cyclobutylidene)ethyl)-N-(P-tolylsulfonyl)amino]-1-oxypropyl]pyrrolidine

5.84 g of 1-[3-(p-tolylsulfonylamino)-1-oxopropyl]pyrrolidine wasdissolved in 300 ml of dry N,N-dimethylformamide under a nitrogenatmosphere. After adding 0.83 g of sodium hydride, the resulting mixturewas stirred for 30 minutes. Then 4.76 g of 2-bromoethylidenecyclobutanewas added thereto and the resulting mixture was stirred at 90° C. for 3hours. After adding 500 ml of water and 500 ml of ethyl acetate, theorganic layer was washed with water, dried over anhydrous magnesiumsulfate and filtered. After distilling off the solvent under reducedpressure, the residue was purified by silica gel column chromatography(eluting with methanol/methylene chloride) to thereby give 6.78 g of thetitle compound as a yellow oily substance.

¹H-NMR(CDCl₃) δ ppm; 1.63(d, J=1 Hz, 3H), 1.65(d, J=1 Hz, 3H), 1.86(m,2H), 1.96(m, 2H), 2.42(s, 3H), 2.68(t, J=8 Hz, 2H), 3.38(t, J=8 Hz, 2H),3.44(t, J=7 Hz, 4H), 3.80(d, J=7 Hz, 2H), 4.98(t, sept, J=1, 7 Hz, 1H),7.29(d, J=8 Hz, 2H), 7.69(d, J=8 Hz, 2H)

Production Example 9 3-(p-Tolylsulfonyl)-6-oxo-3-azabicyclo[3.3.1]heptane-7-spiro-cyclobutane

7.56 g of trifluoromethanesulfonic acid was dissolved in 180 ml of dry1,2-dichloroethane in a nitrogen atmosphere. Into the solution thusobtained was added dropwise 6.77 g of1-[3-[N-(2-cyclobutylidene)ethyl)-N-(p-tolylsulfonyl)amino]-1-oxopropyl]pyrrolidinein 180 ml of 1,2-dichloroethane. Further, 2.37 g of collidine in 180 mlof 1,2-dichloroethane was added dropwise thereinto and the resultingmixture was heated under reflux at 90° C. for 2 hours. After distillingoff the solvent under reduced pressure, the residue was dissolved in 300ml of water and 300 ml of carbon tetrachloride and then heated to 100°C. under a nitrogen atmosphere for 3 hours. The solvent was decanted andthe organic layer was dried over anhydrous magnesium sulfate andfiltered. After distilling off the solvent under reduced pressure, theresidue was purified by silica gel column chromatography (eluting withn-hexane/ethyl acetate) to thereby give 3.41 g of the title compound asan orange oily substance.

¹H-NMR(CDCl₃) δ ppm; 1.89(m, 4H), 2.01(m, 2H), 2.44(s, 3H), 2.85(s, 2H),3.77(dd, J=2, 10 Hz, 2H), 3.89(dd, J=2, 10 Hz, 2H), 7.31(d, J=8 Hz, 2H),7.69(d, J=8 Hz, 2H)

Production Example 10 1,3,5-Trimethyl-3-azabicyclo[3.3.1]nonan-9-one

To 1 l of a solution of 25 g of 2,6-dimethylcyclohexanone in acetic acidwere added 13.5 g of methylamine hydrochloride and 32.4 g of formalin(37% aqueous solution) and the resulting mixture was heated to 100° C.for 2 hours. After removing the solvent under reduced pressure, theobtained residue was distributed between ethyl acetate and an aqueoussolution of potassium carbonate. The organic layer was extracted anddried over anhydrous sodium sulfate. Then the residue was purified bysilica gel column chromatography (eluting with ethyl acetate/n-hexane)to thereby give 19 g of the title compound as a colorless oilysubstance.

¹H-NMR(CDCl₃) δ ppm; 0.92(s, 6H), 1.36-1.45(m, 1H), 1.66-1.76(m, 2H),2.02-2.09(m, 2H), 2.16(s, 3H), 2.17-2.22(m, 2H), 2.92-2.98(m, 2H),3.02-3.17(m, 1H)

Production Example 111,3,5-Trimethyl-9-methoxymethylene-3-azabicyclo[3.3.1]nonane

100 ml of a solution of 20.5 ml of (methoxymethyl)trimethylsilane in drytetrahydrofuran was cooled under a nitrogen atmosphere. Then 92 ml of a1.3 M solution of s-butyllithium in cyclohexane was added dropwisethereinto at −78° C. After the completion of the addition, the mixturewas stirred at −35° C. for 30 minutes. After adding 10.9 g of1,3,5-trimethyl-3-azabicyclo[3.3.1]nonan-9-one, the resulting mixturewas stirred at room temperature for 2 hours and then poured into acooled aqueous solution of ammonium chloride. Then it was made alkalineby adding potassium carbonate and extracted with ethyl acetate. Theorganic layer was washed with water and dried over anhydrous sodiumsulfate. After distilling off the solvent under reduced pressure, 9.2 gof the title compound was obtained as a pale-brown oily substance.

¹H-NMR(CDCl₃) δ ppm; 0.83(s, 3H), 1.15(s, 3H), 1.20-1.37(m, 2H),1.42-1.59(m, 2H), 1.62-1.68(m, 1H), 1.69(dd, J=3.3, 10.7 Hz, 1H),1.86(dd, J=3.3, 10.7 Hz, 1H), 1.99(s, 3H), 2.50(d, J=10.7 Hz, 1H),2.61(d, J=10.7 Hz, 1H), 2.67-2.83(m, 1H), 3.41(s, 3H), 5.59(s, 1H)

Production Example 12(1,3,5-Trimethyl-3-azabicyclo[3.3.1]non-9-yl)carbaldehyde

9.2 g of 1,3,5-trimethyl-9-methoxymethylene-3-azabicyclo-[3.3.1]nonanewas slowly added dropwise to 30 ml of formic acid at room temperature.After completion of the addition, the formic acid was distilled offunder reduced pressure. Then the residue was distributed between ethylacetate and an aqueous solution of potassium carbonate. The organiclayer was extracted and dried over anhydrous sodium sulfate. Afterdistilling off the solvent under reduced pressure, the residue waspurified by silica gel column chromatography (eluting withn-hexane/ethyl acetate) to thereby give 7.3 g of the title compound as acolorless oily substance.

¹H-NMR(CDCl₃) δ ppm; 0.83(s, 6H), 1.55-1.64(m, 4H), 1.65-1.80(m, 3H),1.73(d, J=7.0 Hz, 1H), 2.08(s, 3H), 2.60(d, J=12.0 Hz, 2H), 2.74-2.91(m,1H), 10.06(d, J=7.0 Hz, 1H)

Production Example 13(6R*,8R*)-(3,6,8-Trimethyl-3-azabicyclo[3.3.1]non-9-yl)carbaldehyde

Into a solution of 19.2 g of (methoxymethyl)triphenyl-phosphoniumchloride in dry tetrahydrofuran (200 ml) was added dropwise 32 ml of a1.6 M solution of n-butyllithium at −70° C. and the resulting mixturewas stirred at 0° C. for 30 minutes. Then a solution of 6 g of(6R*,8R*)-3,6,8-trimethyl-3-azabicyclo[3.3.1]nonan-9-one in drytetrahydrofuran (30 ml) was dropped into the reaction mixture and themixture was stirred at room temperature overnight. After adding ethylacetate, the reaction mixture was washed with water and the organiclayer was dried over anhydrous magnesium sulfate. After distilling offthe solvent under reduced pressure, a yellow oily substance wasobtained.

To a solution of this oily substance in acetone (50 ml) was added 15 mlof a 6 N aqueous solution of hydrochloric acid and the resulting mixturewas stirred at room temperature for 4 hours. Then the reaction mixturewas made alkaline by adding a 1 N aqueous solution of sodium hydroxideand extracted with ethyl acetate. The organic layer was dried overanhydrous magnesium sulfate and the solvent was distilled off underreduced pressure. Then the residue was purified by silica gel columnchromatography (eluted with n-hexane/ethyl acetate) to thereby give 2.0g of the title compound as a pale yellow oily substance.

¹H-NMR(CDCl₃) δ ppm; 1.02(d, J=6.8 Hz, 6H), 1.50-2.00(m, 7H),2.08-2.15(m, 2H), 2.24(br.s, 3H), 2.68-2.80(m, 2H), 9.85(s, 1H)

Production Example 14 3-Methyl-9-methylene-3-azabicyclo[3.3.1]nonane

To a solution of 6.9 g of methyltriphenyl phosphonium bromide in toluene(30 ml) was added 2.2 g of potassium tert-butoxide at 0° C. and theresulting mixture was stirred for 30 minutes. Next, 3.0 g of3-methyl-3-azabicyclo[3.3.1]nonan-9-one was added thereto and themixture was reacted for 1 hour. After adding ether, the reaction mixturewas washed with a saturated aqueous solution of sodium chloride anddried over anhydrous magnesium sulfate. After filtering andconcentrating, the residue was purified by silica gel columnchromatography (eluted with ether/n-hexane) to thereby give 3.1 g of thetitle compound as a yellow oily substance.

¹H-NMR(CDCl₃) δ ppm; 1.40-1.50(m, 1H), 1.65-1.80(m, 2H), 1.80-2.00(m,2H), 2.13(s, 3H), 2.1-2.4(m, 4H), 2.45-2.65(m, 1H), 2.83-2.98(m, 2H),4.58(s, 2H)

Production Example 153-(tert-Butoxycarbonyl)-9-methylene-3-azabicyclo[3.3.1]nonane

1.0 g of 3-methyl-9-methylene-3-azabicyclo[3.3.1]nonane was dissolved in1,2-dichloroethane (5 ml). After adding 1.37 g of 1-chloroethylchloroformate, the resulting mixture was heated under reflux at 110° C.for 2 hours. After distilling off the solvent under reduced pressure,methanol was added to the residue and the mixture was heated underreflux for 1 hour. After distilling off the solvent under reducedpressure, 1.0 g of brown crude crystals were obtained. These crystalswere dissolved in 30 ml of methanol and 1.8 ml of triethylamine and 1.7g of di-tert-butyl dicarbonate were added thereto. After reacting atroom temperature for 1 hour, water was added to the reaction mixture.Then the mixture was extracted with ethyl acetate, washed with dilutehydrochloric acid and a saturated aqueous solution of potassiumhydrogencarbonate and dried over anhydrous magnesium sulfate. Afterconcentrating under reduced pressure, the residue was purified by silicagel column chromatography (eluted with ethyl acetate/n-hexane) tothereby give 0.8 g of the title compound as a yellow oily substance.

¹H-NMR(CDCl₃) δ ppm; 1.47(s, 9H), 1.6-2.0(m, 6H), 2.33(br.s, 1H),2.39(br.s, 1H), 2.95(br.d, J=13 Hz, 1H), 3.04(br.d, J=13 Hz, 1H),4.13(d, J=12 Hz, 1H), 4.27(d, J=12 Hz, 1H), 4.67(s, 2H)

Production Example 163-(tert-Butoxycarbonyl)-3-azabicyclo[3.3.1]nonane-9-spirocyclobutan-3′-one

To 3.7 g of zinc/copper alloy was added a solution of 1.4 g of3-(tert-butoxycarbonyl)-9-methylene-3-azabicyclo[3.3.1]-nonane in dryether (30 ml). Subsequently, a solution of 2.6 ml of trichloroacetylchloride in dry dimethoxyethane (50 ml) was dropped thereinto and theresulting mixture was reacted at room temperature for 3 hours. Then asaturated aqueous solution of sodium hydrogencarbonate was added to thereaction mixture while maintaining the mixture at 0° C. or below. Afterfiltering off the zinc/copper alloy, the filtrate was extracted withethyl acetate, washed with a saturated aqueous solution of sodiumchloride and dried over anhydrous magnesium sulfate. After concentratingunder reduced pressure, the residue was purified by silica gel columnchromatography (eluted with ethyl acetate/n-hexane) to thereby give 1.5g of a yellow oily substance. This product was dissolved in 40 ml of asaturated solution of ammonium chloride in methanol. After adding 1.7 gof zinc, the resulting mixture was reacted at room temperature for 24hours. After filtering off the zinc, water was added to the residue.Next, it was extracted with ethyl acetate, washed with a saturatedaqueous solution of sodium chloride and dried over anhydrous magnesiumsulfate. After concentrating, the residue was purified by silica gelcolumn chromatography (eluted with ethyl acetate/n-hexane) to therebygive 0.8 g of the title compound as a colorless oily substance.

¹H-NMR(CDCl₃) δ ppm; 1.47(s, 9H), 1.55-1.90(m, 8H), 2.8-2.95(m, 4H),3.06(d, J=14 Hz, 1H), 3.15(d, J=14 Hz, 1H), 4.02(d, J=13 Hz, 1H),4.15(d, J=13 Hz, 1H)

Production Example 16′(6R*,8R*)-3-(tert-Butoxycarbonyl)-6,8-dimethyl-3-azabicyclo[3.3.1]-nonane-9-spirocyclobutan-3′-one

The title compound was obtained by treating(±)-(6R*,8R*)-3,6,8-trimethyl-3-azabicyclo[3.3.1]nonan-9-one by the samemethods as those of Production Examples 14, 15 and 16.

¹H-NMR(CDCl₃) δ ppm; 1.01-1.13(m, 6H), 1.3-1.95(m, 5H), 1.45(s, 9H),2.65-3.0(m, 3H), 2.89(s, 4H), 3.7-3.85(m, 1H), 3.9-4.0(m, 1H)

Production Examples 17 to 24

The following unsaturated esters were obtained by the same method as theone of Example 19.

TABLE 3 Prodn. Ex. Structural formula NMR 17

¹H-NMR(CDCl₃) δ ppm: 0.9, 0.95(d, J=7Hz, total 3H), 1.0- 1.2(m, 1H),1.26(t, J=7Hz 3H), 1.5- 2.0(m, 2H), 2.14(s, 3H), 2.0-2.3(m, 4H),2.6-2.8(m, 1H), 2.85-3.0(m, 2H), 3.70-3.90(s, total 1H), 4.15(q, J=7Hz,2H), 5.59, 5.74(s, total 1H) 18

¹H-NMR(CDCl₃) δ ppm: 1.29(t, J=7Hz, 3H), 1.69(m, 3H), 1.7- 2.0(m, 2H),2.15- 2.30(m, 1H), 2.25(s, 3H), 2.48(m, 1H), 2.8-2.9(m, 2H), 3.75(m,1H), 4.17(q, J=7Hz, 2H), 5.64(s, 1H) 19

¹H-NMR(CDCl₃) δ ppm: 1.2-1.4(m, 3H), 1.83(s, 1H), 2.26(s, 4H), 2.45(d,J=8Hz, 2H), 3.14-3.23(m, 2H), 3.78(d, J=8Hz, 2H), 3.98(s, 1H),4.1-4.25(m, 3H), 5.74(s, 1H) 20

¹H-NMR(CDCl₃) δ ppm: 1.26(t, J=6.8Hz, 3H), 2.25(s, 3H), 2.34-2.41(m,2H), 2.49-2.54(m, 1H), 2.74-2.81(m, 2H), 2.78(d, J=4.2Hz, 2H),2.83-2.89(m, 2H), 3.49(d, J=14.2Hz, 1H), 3.53(d, J=14.2Hz, 1H), 4.13(q,J=6.8Hz, 2H), 4.18- 4.25(m, 1H), 5.71(s, 1H), # 7.20-7.36(m, 5H) 21

¹H-NMR(CDCl₃) δ ppm: 1.28(t, J=7.2Hz, 3H), 1.32-1.43(m, 2H),1.60-1.72(m, 3H), 1.78-1.94(m, 3H), 1.99-2.05(m, 1H), 2.05-2.10(m, 1H),2.17(s, 3H), 2.51-2.58(m, 1H), 2.60-2.66(m, 2H), 3.93-4.00(m, 1H),4.14(q, J=7.2Hz, 2H), 5.65(s, 1H)

TABLE 4 Prodn. Ex. Structural formula NMR 22

¹H-NMR(CDCl₃) δ ppm: 0.78(d, J=4.6Hz, 3H), 1.28(t, J=6.4Hz, 3H), 1.30-1.43(m, 2H), 1.90- 2.10(m, 2H), 2.14(s, 3H), 2.18-2.32(m, 4H),2.93-3.10(m, 3H), 4.15(q, J=6.4Hz, 2H), 5.62(s, 1H) 23

¹H-NMR(CDCl₃) δ ppm: 0.89(s, 3H), 0.95(s, 3H), 1.28(t, J=7.0Hz, 3H),1.69- 1.81(m, 2H), 1.84- 1.91(m, 2H), 2.00- 2.09(m, 2H), 2.21(s, 3H),2.35-2.43(m, 1H), 2.71-2.81(m, 2H), 4.00-4.07(m, 1H), 4.16(q, J=7.0Hz,2H), 5.73(s, 1H) 24

¹H-NMR(CDCl₃) δ ppm: 0.8 & 0.84(s, 9H(1:1)), 1.29(t, J=7.2Hz, 3H), 1.45-1.58(m, 1H), 1.60- 1.72(m, 1H), 1.94- 2.07(m, 3H), 2.13 & 2.20(s,3H(1:1)), 2.18-2.40(m, 2H), 2.70-2.97(m, 3H), 3.92-4.04(m, 1H), 4.15(q,J=7.2Hz, 2H), 5.61 & 5.64(s, 1H(1:1))

Production Example 25Ethyl[[3-(p-tolylsulfonyl)-3-azabicyclo[3.3.1]heptane-7-spiro-cyclobutan]-6-ylidene]acetate

To a solution of 1.61 g of triethyl phosphonoacetate in drytetrahydrofuran (40 ml) was added 0.288 g of sodium hydride (oily: 60%or above) and the resulting mixture was stirred at room temperature for20 minutes. Then a solution of 1.83 g of3-(p-tolylsulfonyl)-6-oxo-3-azabicyclo[3.3.1]heptane-7-spiro-cyclobutanein tetrahydrofuran (10 ml) was added thereto and the resulting mixturewas reacted for 2 hours. After distilling off the solvent under reducedpressure, the residue was poured into a 0.1 N aqueous solution of sodiumhydroxide and extracted with ethyl acetate. The extract was dried overanhydrous magnesium sulfate and distilled off under reduced pressure.The residue was purified by silica gel column chromatography (elutedwith ethyl acetate/n-hexane) to thereby give 2.1 g of the title compoundas a colorless oily substance.

¹H-NMR(CDCl₃) δ ppm; 1.26(t, J=7 Hz, 3H), 1.66(m, 2H), 1.77(m, 2H),1.94(m, 2H), 2.42(s, 3H), 2.73(td, J=3, 6 Hz, 1H), 3.35(m, 1H), 3.62(dd,J=3, 10 Hz, 1H), 3.69(d, J=2 Hz, 1H), 3.71(t, J=2 Hz, 1H), 3.81(dd, J=3,10 Hz, 1H), 4.12(q, J=7 Hz, 2H), 5.58(s, 1H), 7.26(d, J=8 Hz, 2H),7.67(d, J=8 Hz, 2H)

Production Examples 26 to 32

The following saturated esters were obtained by the same method as theone of Example 20.

TABLE 5 Prodn. Ex. Structural formula NMR 26

¹H-NMR(CDCl₃) δ ppm: 1.26(t, J=7Hz, 3H, anti), 1.26(t, J=7Hz, 3H, syn),1.65-1.80(m, 4H, anti and syn), 1.90-2.06(m, 3H, anti and syn), 2.09(d,J=10Hz, 2H, anti), 2.17(d, J=8Hz, 2H, anti), 2.22(s, 3H, anti), 2.25(s,3H, syn), 2.34(d, J=11Hz, 2H, syn), 2.48(dd, J=4, # 11Hz, 2H, syn),2.57(d, J=8Hz, 2H, syn), 2.72(dd, J=4, 11Hz, 2H, anti), 4.14(q, J=7Hz,2H, syn and anti)

TABLE 6 Prodn. Ex. Structural formula NMR 27

¹H-NMR(CDCl₃) δ ppm: 0.81(d, J=6.8Hz, 3H), 1.25-1.36(m, 2H), 1.26(t,J=7.2Hz, 3H), 1.62-1.70(m, 2H), 1.90-2.04(m, 2H), 2.14(s, 3H), 2.12-2.24(m, 2H), 2.41(d, J=7.2Hz, 2H), 2.54- 2.74(m, 2H), 2.83- 2.92(m, 2H),4.13(q, J=7.2Hz, 2H) 28

¹H-NMR(CDCl₃) δ ppm: 1.21(t, J=7Hz, 3H), 1.40(m, 1H), 1.52(m, 1H),1.66-1.80(m, 2H), 2.04-2.06(m, 4H), 2.22(m, 2H), 2.42- 2.52(m, 4H),3.42- 3.55(m, 4H), 4.26(q, J=7Hz, 2H), 7.30(m, 2H), 7.71(m, 2H) 29

¹H-NMR(CDCl₃) δ ppm: 0.83 & 0.84(s, 9H)(1:1)), 1.26(t, J=7.2Hz, 3H),1.30- 1.62(m, 4H), 1.68- 2.00(m, 6H), 2.12 & 2.14(s, 3H(1:1)), 2.36(d,J=7.2Hz, 1H), 2.47(d, 7.2Hz, 1H), 2.52-2.57(m, 1H), 2.81-2.86(m, 1H),4.13(q, J=7.2Hz, 2H)

TABLE 7 Prodn. Ex. Structural formula NMR 30

¹H-NMR(CDCl₃) δ ppm: 0.98(s, 3H), 1.25(t, J=7.0Hz, 3H), 1.32(s, 3H),1.32-1.40(m, 2H), 1.64-1.72(m, 4H), 1.81-1.88(m, 1H), 2.12(s, 3H), 2.12-2.18(m, 2H), 2.35(d, J=7.6Hz, 2H), 2.68- 2.73(m, 2H), 4.12(q, J=7.0Hz,2H) 31

¹H-NMR(CDCl₃) δ ppm: 1.03(d, J=8Hz, 3H), 1.25(t, J=5Hz, 3H), 1.1-1.3(m,1H), 1.4- 1.7(m, 3H), 1.8-2.0(m, 3H), 2.0-2.30(m, 5H), 2.35-2.43(m, 3H),2.6- 2.9(m, 2H), 4.0-4.1(m, 2H) 32

¹H-NMR(CDCl₃) δ ppm: 1.2-1.3(m, 3H), 1.56(br.s, 1H), 2.06- 2.16(m, 1H),2.24- 2.30(m, 3H), 2.30- 2.38(m, 2H), 2.42- 2.52(m, 1H), 2.6- 2.68(m,2H), 3.12(br.d, J=11Hz, 2H), 3.81(d, J=12Hz, 2H), 3.9-3.98(m, 2H),4.1-4.2(m, 2H)

Production Example 33Ethyl(3-methyl-7-phenyl-3-azabicyclo[3.3.1]non-9-yl)acetate

The title compound was obtained by treating 4-phenylcyclohexanone by thesame methods as those of Examples 19 and 20.

¹H-NMR(CDCl₃) δ ppm; 1.28(t, J=7.2 Hz, 3H), 1,70-2.34(m, 10H), 2.22(s,3H), 2.59(d, J=7.2 Hz, 2H), 2.5-2.70(m, 1H), 2.92-3.04(m, 1H), 4.16(q,J=7.2 Hz, 2H), 7.12-7.38(m, 5H)

Production Example 34(3-Methyl-3-azabicyclo[3.3.1]nonan-9-yl)carbonitrile

6.2 g of 3-methyl-3-azabicyclo[3.3.1]nonan-9-one was dissolved in 150 mlof dry dimethoxyethane and 40 ml of tert-butanol. Then 46 g of potassiumtert-butoxide and 15.8 g of tosylmethyl isocyanide were added thereto at0° C. After stirring for 30 minutes, the resulting mixture was heatedunder reflux for 3 hours. Then the reaction mixture was brought back toroom temperature and water was added thereto. The resulting mixture wasextracted with ethyl acetate, washed with a saturated aqueous solutionof sodium chloride and dried over anhydrous magnesium sulfate. Afterconcentrating under reduced pressure, the obtained residue was purifiedby silica gel column chromatography (eluted with ethyl acetate/n-hexane)to thereby give 5.5 g of the title compound as a yellow oily substance.

¹H-NMR(CDCl₃) δ ppm;

One Isomer

1.45-1.60(m, 1H), 1.55-1.70(m, 2H), 1.7-1.8(m, 2H), 1.95-2.1(m, 2H),2.14(s, 3H), 2.18(d, J=10 Hz, 2H), 2.4-2.6(m, 1H), 2.64(s, 1H), 2.93(d,J=10 Hz, 2H)

Other Isomer

1.4-1.5(m, 1H), 1.54-1.70(m, 2H), 1.84-1.94(m, 2H), 2.04-2.12(m, 2H),2.18(s, 3H), 2.44-2.6(m, 1H), 2.58(d, J=12 Hz, 2H), 2.64-2.68(m, 1H),2.80(d, J=12 Hz, 2H)

Production Example 35Methyl(3-methyl-3-azabicyclo[3.3.1]non-9-yl)carboxylate

To a solution of 5.5 g of(3-methyl-3-azabicyclo[3.3.1]nonan-9-yl)carbonitrile in 20 ml ofethylene glycol was added a solution of 48 g of potassium hydroxide in50 ml of water and the resulting mixture was reacted at 200° C. for 6hours. Then the reaction mixture was brought back to room temperatureand made weakly acidic by adding an aqueous solution of sodiumdihydrogenphosphate. After concentrating under reduced pressure, theresidue was washed with tetrahydrofuran and ethanol and the washingliquor was concentrated. Next, 500 ml of methanol was added thereto.After further adding 10 ml of thionyl chloride, the resulting mixturewas reacted at 70° C. for 3 hours. The reaction mixture was cooled to 0°C. and made alkaline by adding an aqueous solution of sodium hydroxide.Then it was extracted with ethyl acetate, washed with a saturatedaqueous solution of sodium chloride and dried over anhydrous magnesiumsulfate. After concentrating under reduced pressure, the residue waspurified by silica gel column chromatography (eluted with n-hexane/ethylacetate) to thereby give 3.4 g of the title compound as a pale brownoily substance.

¹H-NMR(CDCl₃) δ ppm; 1.3-1.5(m, total 1H), 1.55-1.92(m, total 4H), 2.08and 2.15(s, total 3H), 2.16-2.38(m, total 5H), 2.38-2.58(m, total 1H),2.93 and 2.67(d, J=10 Hz, total 2H), 3.72 and 3.70(s, total 3H)

Production Example 36

The following compound was obtained by the same method as the one ofProduction Example 35.

TABLE 8 Prodn. Ex. Structural formula NMR 36

¹H-NMR(CDCl₃) δ ppm: 1.64-1.76(m, 4H), 2.05(s, 1H), 2.08(s, 1H), 2.24(s,3H), 2.30(s, 1H), 2.50(br.s, 2H), 2.75(dd, J=4, 11Hz, 2H), 3.66(s, 3H)

Production Examples 37 to 39

The following compounds were obtained by the same method as the one ofProduction Example 25.

TABLE 9 Prodn. Ex. Structural formula NMR 37

¹H-NMR(CDCl₃) δ ppm: 1.03(d, J=6.8Hz, 3H), 1.05(d, J=6.8Hz, 3H), 1.31(t,J=7.2Hz, 3H), 1.44-1.63(m, 7H), 1.85(s, 3H), 2.35(t, J=6.8Hz, 2H),2.75(d, J=12.8Hz, 1H), 2.83(d, J=12.8Hz, 1H), 3.98(d, J=12.8Hz, 1H),4.03(d, J=12.8Hz, 1H), 4.21(q, J=7.2Hz, 2H), 4.43(d, J=6.4Hz, # 1H),4.78(d, J=14.4Hz, 1H), 6.73(t, J=6.8Hz, 1H), 7.21(dd, J=6.4, 14.4Hz, 1H)38

¹H-NMR(CDCl₃) δ ppm: 1.00(d, J=6.8Hz, 3H), 1.04(d, J=6.8Hz, 3H), 1.30(t,J=7.2Hz, 3H), 1.22-1.33(m, 2H), 1.42- 1.64(m, 4H), 1.88-2.40(m, 1H),2.38(t, J=6.8Hz, 2H), 2.72-2.86(m, 2H), 3.95- 4.07(m, 2H), 4.22(q,J=7.2Hz, 2H), 4.40-4.50(m, 1H), 4.78(d, J=14Hz, 1H), 5.82(d, # J=15.6Hz,1H), 6.89(td, J=6.8, 15.6Hz, 1H), 7.21(dd, J=6.4, 14Hz, 1H) 39

¹H-NMR(CDCl₃) δ ppm: 1.31(t, J=7.1Hz, 3H), 1.49(m, 1H), 1.58-1.85(m,8H), 1.89(d, J=1.3Hz, 3H), 2.40(t, J=7.1Hz, 2H), 3.10(m, 1H), 3.18(m,1H), 4.16-4.26(m, 4H), 4.45(dd, J=1.6, 6.2Hz, 1H), 4.79(dd, J=1.6,13.9Hz, 1H), 6.74(m, 1H), 7.25(dd, J=6.2, 13.9Hz, 1H)

Production Examples 40 to 43

The following compounds were obtained by the same methods as those ofProduction Example 25 and Example 20.

TABLE 10 Prodn. Ex. Structural formula NMR 40

¹H-NMR(CDCl₃) δ ppm: 0.80-1.00(m, 4H), 1.01(d, J=7.2Hz, 6H), 1.26(t,J=7.2Hz, 3H), 1.40-1.48(m, 2H), 1.78(q, J=7.6Hz, 2H), 1.78-1.95(m, 2H),2.04- 2.12(m, 1H), 2.19(br.s, 3H), 2.31(t J=7.6Hz, 2H), 2.55-2.67(m,2H), 4.13(q, J=7.2Hz, 2H) 41

¹H-NMR(CDCl₃) δ ppm: 0.80-1.05(m, 4H), 1.00(d, J=7.2Hz, 3H), 1.02(d,J=7.2Hz, 3H), 1.13(d, J=6.8Hz, 3H), 1.26(t, J=6.8Hz, 3H), 1.20-1.95(m,7H), 2.19(br.s, 3H), 2.40- 2.68(m, 3H), 4.13(q, J=6.8Hz, 2H) 42

¹H-NMR(CDCl₃) δ ppm: 1.2-1.9(m, 10H), 1.24(t, J=7Hz, 3H), 1.45(s, 9H),2.17-2.33(m, 2H), 2.39(d, J=7Hz, 2H), 2.4-2.6(m, 1H), 2.9-3.25(m, 2H),3.82(t, J=14Hz, 1H), 3.95(t, 13Hz, 1H), 4.11(q, J=7Hz, 2H) 43

¹H-NMR(CDCl₃) δ ppm: 0.95-1.15(m, 6H), 1.24(t, J=5Hz, 3H), 1.43(s, 9H),1.2-1.6(m, 8H), 2.1- 2.25(m, 2H), 2.38(d, J=8Hz, 2H), 2.5-2.65(m, 1H),2.6-2.9(m, 2H), 3.5- 3.65(m, 2H), 4.09(q, J=5Hz, 2H)

Production Example 44

The following compound was obtained by the same methods as those ofExamples 19 and 12.

TABLE 11 Prodn. Ex. Structural formula NMR 44

¹H-NMR(CDCl₃) δ ppm: 1.35(t, J=7.7Hz, 3H), 1.50-1.58(m, 1H), 1.74-1.98(m, 3H), 2.00-2.09(m, 2H), 3.07-3.23(m, 3H), 3.81-3.88(m, 1H),4.30(q, J=7.7Hz, 2H), 4.31-4.38(m, 2H), 4.48(dd, J=1.7, 5.9Hz, 1H),4.82(dd, J=1.7, 14.7Hz, 1H), 7.25(dd, J=5.9, 14.7Hz, 1H)

Production Example 45 Ethyl3-[3-(vinyloxycarbonyl)-1,5-dimethyl-3-azabicyclo[3.3.1]non-9-yl]-2-methylpropenoate

The title compound was obtained by treating (1,3,5-trimethyl-3-azabicyclo [3.3.1]-non-9-yl)carbaldehyde by the samemethods as those of Production Example 25 and Example 12.

¹H-NMR(CDCl₃) δ ppm;

0.73(s, 6H), 1.32(t, J=7.0 Hz, 3H), 1.42-1.51(m, 2H), 1.54-1.70(m, 3H),1.72-1.88(m, 1H), 1.90(d, J=1.9 Hz, 3H), 2.18(d, J=11.4 Hz, 1H), 2.70(d,J=11.3 Hz, 1H), 2.78(d, J=11.3 Hz, 1H), 4.00(d, J=13.1 Hz, 1H), 4.07(d,J=13.1 Hz, 1H), 4.21(q, J=7.0 Hz, 2H), 4.46(dd, J=1.7, 5.9 Hz, 1H),4.80(dd, J=1.7, 14.7 Hz, 1H), 6.93(qd, J=1.9, 11.4 Hz, 1H), 7.25(dd,J=5.9, 14.7 Hz, 1H)

Production Example 46Ethyl[3-(vinyloxycarbonyl)-3-azabicyclo[3.3.1non-9-yl]fluoroacetate

The title compound was obtained by treating3-methyl-3-azabicyclo[3.3.1]nonan-9-one by the same methods as those ofProduction Example 25 and Examples 20 and 12 with the use of anappropriate Horner-Emmons reagent.

¹H-NMR(CDCl₃) δ ppm; 1.32(t, J=7.4 Hz, 3H), 1.51-1.59(m, 1H),1.64-1.94(m, 6H), 2.06-2.18(m, 2H), 3.05-3.12(m, 1H), 3.14-3.21(m, 1H),4.16-4.33(m, 2H), 4.28(q, J=7.4 Hz, 2H), 4.46(dd, J=1.8, 6.3 Hz, 1H),4.79(dd, J=1.8, 14.0 Hz, 1H), 5.17(dd, J=10.4, 49.2 Hz, 1H), 7.25(dd,J=6.3, 14.0 Hz, 1H)

Production Example 47 Ethyl(syn)-(6R*,7R*)-[6,7-dimethyl-3-(vinyloxycarbonyl)-3-azabicyclo[3.2.1]oct-8-yl]acetate

The title compound was obtained by treatingethyl(6R*,7R*)-[3,6,7trimethyl3-azabicyclo[3.2.1]oct-8-ylidene]acetateby the same methods as those of Examples 10, 11 and 12.

¹H-NMR(CDCl₃) δ ppm; 0.98, 1.05(d, J=7.0 Hz, total 3H), 0.99, 1.06(d,J=7.1 Hz, total 3H), 1.26(t, J=7.1 Hz, 3H), 1.37-1.45(m, 1H),1.53-1.63(m, 1H), 1.67-1.74(m, 1H), 1.84-1.94(m, 1H), 2.29-2.37(m, 1H),2.48-2.62(m, 2H), 3.06, 3.14(dd, J=2.4, 13.7 Hz, total 1H), 3.13,3.22(dd, J=2.0, 13.0 Hz, total 1H), 3.60, 3.63(t, J=2.7 Hz, total 1H),3.82, 3.86(br.m, total 1H), 4.15(q, J=7.1 Hz, 2H), 4.44, 4.45(dd, J=1.5,6.2 Hz, total 1H), 4.76, 4.79(dd, J=1.5, 13.9 Hz, total 1H), 7.23,7.24(dd, J=6.2, 13.9 Hz, total 1H)

Production Example 48Ethyl(3-methyl-9-oxo-3-azabicyclo[3.3.1]non-1-yl)carboxylateethylenedithioketal

5.0 g of ethyl(3-methyl-9-oxo-3-azabicyclo[3.3.1]non-1-yl)carboxylateand 2.8 ml of 1,2-ethanedithiol were dissolved in methylene chloride (45ml) and ice-cooled. Then 4.1 ml of a boron trifluoride/diethyl ethercomplex was dropped thereinto and the resulting mixture was stirred atroom temperature for 5 days. The reaction mixture was concentrated and 1N sodium hydroxide was added thereto. After extracting with ethylacetate, the ethyl acetate layer was washed with 1 N sodium hydroxide,water and a saturated aqueous solution of sodium chloride, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(eluted with n-hexane/ethyl acetate) to thereby give 2.42 g of the titlecompound as a colorless oily substance.

¹H-NMR(CDCl₃) δ ppm; 1.26(t, J=7.1 Hz, 3H), 1.46(m, 1H), 1.82(m, 1H),1.91-2.02(m, 2H), 2.18(s, 3H), 2.20(m, 1H), 2.48(m, 1H), 2.59-2.86(m,4H), 3.05(dd, J=0.9, 12.1 Hz, 1H), 3.15-3.25(m, 4H), 4.13(m, 2H)

Production Example 49 Ethyl(3-methyl-3-azabicyclo[3.3.1]non-1-yl)carboxylate

2.42 g of ethyl(3-methyl-9-oxo-3-azabicyclo[3.3.1]non-1-yl)carboxylateethylenedithioketal was dissolved in ethanol (200 ml). After adding 40 gof Raney nickel, the resulting mixture was heated under reflux for 2hours. Then the reaction mixture was filtered and concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (eluted with toluene/ethyl acetate) to thereby give 0.95g of the title compound as a slightly yellow oily substance.

¹H-NMR(CDCl₃) δ ppm; 1.24(t, J=7.1 Hz, 3H), 1.46-1.63(m, 3H),1.64-1.78(m, 3H), 1.90-1.99(m, 2H), 2.06-2.18(m, 5H), 2.59(m, 1H),2.78(m, 1H), 3.02(m, 1H), 4.10(q, J=7.1 Hz, 2H)

Production Example 50 Ethyl(3-methyl-3-azabicyclo[3.3.1]non-1-yl)acetate

1.1 ml of dibromomethane was dissolved in tetrahydrofuran (20 ml) andcooled to −90° C. Into the solution thus obtained were dropped 9.77 mlof a 1.6 M solution of n-butyllithium in hexane and 20 ml of a solutionof lithium 2,2,6,6-tetramethylpiperidide, which had been prepared from2.88 ml of 2,2,6,6-tetramethylpiperidine, in tetrahydrofuran whilemaintaining the bulk temperature at 10° C. or below. 5 minutesthereafter, 10 ml of a solution of 1.0 g of ethyl(3-methyl-3-azabicyclo[3.3.1]non-1-yl)carboxylate in tetrahydrofuran wasdropped thereinto. After 20 minutes, 0.8 ml of2,2,6,6-tetramethylpiperidine was added thereto. 5 minutes thereafter,23.7 ml of a 1.6 M solution of n-butyllithium in hexane was droppedthereinto and the resulting mixture was stirred. After 10 minutes, thereaction mixture was heated to 30° C. and stirred for 1 hour. Then thereaction mixture was quickly dropped into a solution of hydrogenchloride prepared from 25 ml of acetyl chloride and 250 ml of ethanoland stirred at room temperature for 14 hours. The reaction mixture wasconcentrated and an aqueous solution of potassium carbonate was addedthereto followed by the extraction with ethyl acetate. The ethyl acetatelayer was washed with water and a saturated aqueous solution of sodiumchloride and dried over anhydrous sodium sulfate. After concentratingunder reduced pressure, the residue was purified by silica gel columnchromatography (eluted with n-hexane/ethyl acetate) to thereby give 0.63g of the title compound as a slightly yellow oily substance.

¹H-NMR(CDCl₃) δ ppm; 1.26(t, J=7.1 Hz, 3H), 1.34(m, 1H), 1.40-1.60(m,4H), 1.68-1.78(m, 2H), 1.83-1.93(m, 2H), 2.06(m, 1H), 2.07(s, 2H),2.11(s, 3H), 2.56(m, 1H), 2.76-2.86(m, 2H), 4.11(q, J=7.1 Hz, 2H)

Production Example 51 Ethyl(syn)-(3-benzyl-3-azabicyclo[3.3.1]non-7-yl)acetate

The title compound was obtained fromethyl(3-benzyl-3-azabicyclo[3.3.1]non-7-yl)carboxylate by the samemethod as the one of Production Example 50.

¹H-NMR(CDCl₃) δ ppm; 1.03(m, 1H), 1.23(m, 2H), 1.25(t, J=7.1 Hz, 3H),1.77(m, 1H), 1.85-2.09(m, 7H), 2.24(d, J=7.0 Hz, 2H), 2.50-2.58(m, 2H),3.43(s, 2H), 4.13(q, J=7.1 Hz, 2H), 7.20-7.35(m, 5H)

Production Example 52[(anti)-2-[3-(Vinyloxycarbonyl)-3-azabicyclo[3.3.1]-non-9-yl]ethyl]methanesulfonate]

290 mg of(anti)-2-[3-(vinyloxycarbonyl)-3-azabicyclo-[3.3.1]non-9-yl]ethanol wasdissolved in 4 ml of methylene chloride and 0.23 ml of pyridine wasadded thereto followed by ice-cooling. After adding 0.2 ml ofmethanesulfonyl chloride, the resulting mixture was stirred at roomtemperature for 14 hours. Then the reaction mixture was concentrated andthe residue was purified by silica gel column chromatography (elutedwith n-hexane/ethyl acetate) to thereby give 370 mg of the titlecompound as a colorless oily substance.

¹H-NMR(CDCl₃) δ ppm; 1.48(m, 1H), 1.60-1.87(m, 8H), 1.95-2.03(m, 2H),3.03(s, 3H), 3.12(m, 1H), 3.19(m, 1H), 4.18-4.27(m, 2H), 4.30(t, J=6.4Hz, 2H), 4.45(dd, J=1.6, 6.2 Hz, 1H), 4.79(dd, J=1.6, 14.1 Hz, 1H),7.25(dd, J=6.2, 14.1H, 1H)

Production Example 53(anti)-3-[3-(Vinyloxycarbonyl)-3-azabicyclo[3.3.1]non-9-yl]propanenitrile

370 mg of[(anti)-2-[3-(vinyloxycarbonyl)-3-azabicyclo[3.3.1]non-9-yl]ethyl]methanesulfonate was dissolved in dimethyl sulfoxide (3 ml). Afteradding 108 mg of sodium cyanide, the resulting mixture was stirred at80° C. for 2 hours. After adding water, the reaction mixture wasextracted with ethyl acetate. Then the ethyl acetate layer was washedwith water and a saturated aqueous solution of sodium chloride, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. Then the residue was purified by silica gel columnchromatography (eluted with n-hexane/ethyl acetate) to thereby give 167mg of the title compound as a colorless oily substance.

¹H-NMR(CDCl₃) δ ppm; 1.48(m, 1H), 1.61-1.84(m, 8H), 1.87-1.95(m, 2H),2.39(t, J=7.3 Hz, 2H), 3.12(m, 1H), 3.20(m, 1H), 4.20-4.30(m, 2H),4.46(dd, J=1.6, 6.2 Hz, 1H), 4.79(dd, J=1.6, 14.1 Hz, 1H), 7.25(dd,J=6.2, 14.1 Hz, 1H)

Production Example 54 Methyl(anti)-3-(3-azabicyclo[3.3.1]non-9-yl)propanoate

167 mg of(anti)-3-[3-(vinyloxycarbonyl)-3-azabicyclo-[3.3.1]non-9-yl]propanenitrilewas dissolved in ethanol (2 ml). After adding 2 ml of water and 107 mgof potassium hydroxide, the resulting mixture was heated under refluxfor 12 hours. After further adding 2 ml of ethanol and 107 mg ofpotassium hydroxide, the resulting mixture was heated under reflux foradditional 10 hours. Then the reaction mixture was concentrated underreduced pressure. After adding 10 ml of 10% hydrogen chloride/methanol,the reaction mixture was heated under reflux for 3 hours and thenconcentrated under reduced pressure. An aqueous solution of potassiumcarbonate was added to the residue followed by the extraction withmethylene chloride. After drying over anhydrous potassium carbonate, itwas concentrated under reduced pressure. Then the residue was purifiedby silica gel column chromatography (eluted with methylenechloride/methanol/conc. aqueous ammonia) to thereby give 97 mg of thetitle compound as a pale brown oily substance.

¹H-NMR(CDCl₃) δ ppm; 1.49-1.67(m, 6H), 1.71-2.03(m, 5H), 2.12(m, 1H),2.31(t, J=7.7 Hz, 2H), 2.96-3.04(m, 2H), 3.12-3.18(m, 2H), 3.68(s, 3H)

Production Examples 55 and 56

The following compounds were obtained by the same method as the one ofExample 27.

TABLE 12 Prodn. Ex. Structural formula NMR 55

¹H-NMR(CDCl₃) δ ppm: 1.11(d, J=7.0Hz, 3H), 1.25(t, J=7.1Hz, 3H),1.38-1.68(m, 6H), 1.77(br.s, 1H), 1.87(m, 1H), 2.09-2.21(m, 5H), 2.42(m,1H), 2.77-2.89 (m, 2H), 2.94(m, 1H), 4.13(q, J=7.1Hz, 2H) 56

¹H-NMR(CDCl₃) δ ppm: 1.24 and 1.25(s, 3H), 1.30-1.38, 1.64-1.70,1.76-1.92, 1.96-1.98, 2.08-2.12(m, 8H), 2.07 and 2.18(s, 3H), 2.30-2.35, 2.38-2.46, 2.58- 2.70(m, 4H), 3.67 and 3.72(s, 3H)

Production Examples 57 to 60

The following compounds were obtained by the same method as the one ofExample 12.

TABLE 13 Prodn. Ex. Structural formula NMR 57

¹H-NMR(CDCl₃) δ ppm: 1.15(d, J=7Hz, 3H), 1.26(t, J=7Hz, 3H),1.45-1.52(m, 1H), 1.58- 1.72(m, 5H), 1.78(br.d, J=11Hz, 1H), 1.84-1.91(m, 2H), 2.84(qd, J=7, 11Hz, 1H), 3.05- 3.20(m, 2H), 4.15- 4.18(q,J=7Hz, 2H), 4.18-4.29(s, 2H), 4.44(dd, J=2, 6Hz, 0.5H), 4.44(dd, # J=2,6Hz, 0.5H), 4.77(dd, J=2, 14Hz, 0.5H), 4.78(dd, J=2, 14Hz, 0.5H),7.22(dd, J=6, 14Hz, 1H) 58

¹H-NMR(CDCl₃) δ ppm: 1.15(d, J=7Hz, 1.5H), 1.17(d, J=7Hz, 1.5H), 1.25(t,J=7Hz, 1.5H), 1.26(t, J=7Hz, 1.5H), 1.43-1.54(m, 2H), 1.64- 1.78(m, 4H),1.82- 1.88(m, 1H), 1.89- 2.01(m, 2H), 2.74(dq, J=7, 9Hz, 1H), 3.16(ddd,J=15, 3, 1Hz), 0.5H), 3.23(ddd, J=1, 3, 14Hz, 0.5H), # 3.36(ddd, J=2, 5,14Hz, 0.5H), 3.43(ddd, J=2, 4, 15Hz, 0.5H), 3.88(m, 2H), 4.14(q, J=7Hz,2H), 4.44(dd, J=1, 6Hz, 1H), 4.78(dd, J=1, 14Hz, 1H), 7.25(dd, J=6,14Hz, 1H) 59

¹H-NMR(CDCl₃) δ ppm: 1.36-1.42(m, 1H), 1.55(s, 3H), 1.64- 1.82(m, 5H),2.12(br.s, 1H), 2.17(br.s, 1H), 3.43(ddd, J=2, 5, 14Hz, 1H), 3.51(ddd, ,J=2, 5, 14Hz, 1H), 3.74(s, 3H), 3.92(dd, J=2, 5Hz, 1H), 3.95(dd, J=2,5Hz, 1H), 4.46(dd, J=2, 6Hz, 1H), 4.80(dd, J=2, 14Hz, 1H), 7.25(dd, #J=6, 14Hz, 1H) 60

¹H-NMR(CDCl₃) δ ppm: 1.45-1.52(m, 1H), 1.55(s, 3H), 1.64- 1.76(m, 3H),1.95(br.s, 2H), 2.12(br.s, 1H), 2.16(br.s, 1H), 3.33(ddd, J=2, 4, 13Hz,1H), 3.35(ddd, J=3, 4, 13Hz, 1H), 3.72(s, 3H), 3.99(br.t, J=13Hz, 2H),4.43(dd, J=2, 6Hz, 1H), 4.77(dd, J=2, 14Hz, 1H), 7.22(dd, J=6, # 14Hz,1H)

Production Example 61Ethyl(11-hydroxy-9-methyl-9-azabicyclo[5.3.1]undec-11-yl)acetate

A solution of 2.1 g of ethyl ethynyl ether (a 50% hexane solution) indry diethyl ether (25 ml) was cooled in a nitrogen atmosphere to −78° C.After dropping 6 ml of a 2.5 M solution of n-butyllithium in hexane, theresulting mixture was stirred for 10 minutes. Next, 10 ml of a solutionof 78 g of 3-methyl-3-azabicyclo[5.3.1]undecan-11-one in dry diethylether (10 ml) was dropped into the reaction mixture. After stirring for15 minutes, the mixture was brought back to room temperature and thendistributed into an aqueous solution of ammonium chloride and ethylacetate. The organic layer was extracted and dried over anhydrous sodiumsulfate. After distilling off the solvent, an oily component wasobtained. Then 100 ml of tetrahydrofuran was added thereto and theresulting mixture was stirred. After dropping 10 mmol of conc. sulfuricacid thereinto, the reaction mixture was distributed into an aqueoussolution of sodium bicarbonate and ethyl acetate and the organic layerwas extracted. After distilling off the solvent under reduced pressure,the residue was purified by silica gel column chromatography (elutedwith ethyl acetate/n-hexane) to thereby give 1.29 g of the titlecompound as a colorless oily substance.

¹H-NMR(CDCl₃) δ ppm; 1.14-1.26(m, 2H), 1.26(t, J=7.2 Hz, 3H),1.50-1.65(m, 3H), 1.68-1.73(m, 2H), 1.77-1.90(m, 3H), 2.02-2.12(m, 2H),2.15(s, 3H), 2.15-2.22(m, 2H), 2.64(d, J=12.6 Hz, 2H), 2.67(s, 2H),3.92(s, 1H), 4.15(q, J=7.2 Hz, 2H)

Production Example 629-(1,3-Dithian-2-ylidenemethyl)-1,3,5-trimethyl-3-azabicyclo[3.3.1]nonane

Into 50 ml of a solution of 2.85 ml of 2-trimethylsilyl-1,3-dithiane indry tetrahydrofuran was dropped 5.2 ml of a 2.5 M solution ofn-butyllithium in hexane at −30° C. After stirring for 30 minutes, 1.93g of (1,3,5-trimethyl-3-azabicyclo[3.3.1]non-9-yl)carbaldehdye was addedthereto and the resulting mixture was stirred at room temperature overday and night. Then the reaction mixture was poured into an aqueoussolution of ammonium chloride, made alkaline with potassium carbonateand extracted with ethyl acetate. The organic layer was washed withwater and dried over anhydrous sodium sulfate. After distilling off thesolvent under reduced pressure, the residue was recrystallized fromn-hexane to thereby give 1.78 g of the title compound as colorlessneedles.

¹H-NMR(CDCl₃) δ ppm; 0.55(s, 6H), 1.14-1.24(m, 2H), 1.24-1.34(m, 3H),1.65(dd,J=2.2, 11.8H, 2H), 1.91(s, 3H), 1.98-2.05(m, 2H), 2.10(d, J=11.0Hz, 1H), 2.42-2.55(m, 1H), 2.49(d, J=11.8 Hz, 2H), 2.65-2.74(m, 4H),6.03(d, J=11.0 Hz, 1H)

Production Example 63Methyl(1.3.5-trimethyl-3-azabicyclo[3.3.1]non-9-yl)acetate

To a solution of 1.78 g of9-(1,3-dithian-2-ylidenemethyl)-1,3,5-trimethyl-3-azabicyclo[3.3.1]nonanein a solvent mixture of methanol (27 ml) with water (3 ml) was added3.53 g of mercuric chloride under stirring and the resulting mixture wasthen refluxed for 20 hours. Next, the reaction mixture was poured intoethyl acetate/an aqueous solution of potassium carbonate and filteredthrough celite. After. distilling off the solvent under reducedpressure, the residue was purified by silica gel column chromatography(eluted with n-hexane/ethyl acetate) to thereby give 0.23 g of the titlecompound as a colorless oily substance.

¹H-NMR(CDCl₃) δ ppm; 0.57(s, 6H), 1.09-1.24(m, 5H), 1.51(t, J=6.0 Hz,1H), 1.70(dd, J=2.5, 11.6 Hz, 2H), 1.90(s, 3H), 2.17(d, J=6.0 Hz, 2H),2.45(d, J=11.6 Hz, 2H), 2.42-2.49(m, 1H), 3.51(s, 3H)

Production Example 64(anti)-2-(3-Methyl-3-azabicyclo[3.3.1]non-9-yl)ethanol

To a solution of 2.8 g of ethyl(anti)-(3-methyl-3-azabicyclo[3.3.1]non-9-yl)acetate in drytetrahydrofuran (50 ml) was added 0.47 g of lithium aluminum hydride at0° C. and the resulting mixture was reacted for 20 minutes. After addinga 10% aqueous solution of sodium hydroxide to the reaction mixture, theinsoluble matters were filtered off and the filtrate was concentratedunder reduced pressure to thereby give 2.5 g of the title compound as acolorless oily substance.

¹H-NMR(CDCl₃) δ ppm; 1.3-1.45(m, 1H), 1.45-1.65(m, 6H), 1.75(q, J=5 Hz,4H), 2.14(s, 3H), 2.0-2.25(m, 2H), 2.3-2.50(m, 1H), 2.83-2.98(m, 2H),3.68(q, J=5 Hz, 2H)

Production Example 65 Methyl4-[2-((anti)-3-methyl-3-azabicyclo[3.3.1]non-9-yl)ethyloxylphenylacetate

To a solution of 0.9 g of(anti)-2-(3-methyl-3-azabicyclo[3.3.1]non-9-yl)ethanol, 1.2 g of methyl4-hydroxyphenylacetate and 1.95 g of triphenylphosphine in drytetrahydrofuran (30 ml) was added 1.2 ml of diethyl azodicarboxylate at0° C. The obtained mixture was reacted for 10 minutes and then stirredat room temperature for 72 hours. After adding water and dilutehydrochloric acid, the reaction mixture was washed with ethyl acetate.Then aqueous ammonia was added to the aqueous layer followed by theextraction with ethyl acetate. The extract was washed with a saturatedaqueous solution of sodium chloride, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluted with ethylacetate/n-hexane) to thereby give 1.0 g of the title compound as acolorless oily substance.

¹H-NMR(CDCl₃) δ ppm; 1.4-1.7(m, 7H), 1.7-1.9(m, 2H), 1.96(q, J=7 Hz,2H), 2.1-2.25(m, 4H), 2.35-2.50(m, 1H), 2.85-2.95(m, 2H), 3.56(s, 2H),3.68(s, 3H), 3.97(t, J=7 Hz, 2H), 6.85(d, J=8 Hz, 2H), 7.18(d, J=8 Hz,2H)

Production Examples 66 and 67

The following compounds were obtained by the same method as the one ofProduction Example 65.

TABLE 14 Prodn. Ex. Structural formula NMR 66

¹H-NMR(CDCl₃) δ ppm: 1.3-1.45(m, 1H), 1.4- 1.6(m, 3H), 1.5-1.65(m, 3H),1.67-1.8(m, 2H), 1.92(q, J=8Hz, 2H), 2.0-2.2(m, 4H), 2.3-2.5(m, 1H),2.8-2.95(m, 2H), 3.85(s, 3H), 3.97(t, J=7Hz, 2H), 7.03(ddd, J=1, 3, 8Hz,1H), 7.27(t, J=8Hz, 1H), 7.48(dd, J=1, 3Hz, 1H), 7.55(ddd, J=1, 3, 8Hz,1H) 67

¹H-NMR(CDCl₃) δ ppm: 1.36(t, J=5Hz, 3H), 1.3- 1.5(m, 1H), 1.5-1.6(m,3H), 1.6-1.7(m, 2H), 1.7-1.9(m, 2H), 1.95-2.05(m, 2H), 2.13(s, 3H),2.19(d, J=10Hz, 2H), 2.35-2.50(m, 1H), 2.93(d, J=10Hz, 2H), 4.04(t,J=5Hz, 2H), 4.33(q, J=5Hz, 2H), 6.90(d, J=8Hz, 2H), 8.00(d, J=8Hz, 2H)

Production Example 68 tert-Butyl[2-((anti)-3-methyl-3-azabicyclo[3.3.1]non-9-yl)ethyloxy]acetate

To 17 ml of a 50% aqueous solution of sodium hydroxide and 5 ml ofmethylene chloride were added 0.7 g of(anti)-2-[3-methyl-3-azabicyclo[3.3.1]non-9-yl]ethanol, 5.6 ml oftert-butyl bromoacetate and 1.3 g of tetrabutylammonium hydrogensulfateand the resulting mixture was vigorously stirred at room temperature for2 hours. After adding dilute hydrochloric acid, the reaction mixture waswashed with ether. Then aqueous ammonia was added thereto and themixture was extracted with ethyl acetate. The extract was washed with asaturated aqueous solution of sodium chloride, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. Thus, 1.3 gof the title compound was obtained as a yellow oily substance.

¹H-NMR(CDCl₃) δ ppm; 1.46(s, 9H), 1.40-1.90(m, 10H), 2.11(s, 3H),2.1-2.2(m, 2H), 2.3-2.5(m, 1H), 2.83-2.95(m, 2H), 3.53(t, J=5 Hz, 2H),3.94(s, 2H)

Production Example 69Ethyl[2-((anti)-3-methyl-3-azabicyclo[3.3.1]non-9-yl)ethyloxy]acetate

To a solution of 1.3 g of tert-butyl[2-((anti)-3-methyl-3-azabicyclo[3.3.1]non-9-yl)ethyloxy]acetate inmethylene chloride (10 ml) was added 3.92 ml of trifluoroacetic acid andthe resulting mixture was reacted at 50° C. for 30 minutes. Then thereaction mixture was concentrated under reduced pressure to thereby give1.0 g of a crude carboxylic acid as a yellow oily substance. To 1.0 g ofthis crude carboxylic acid was added 100 ml of ethanol. Next, 3 ml ofthionyl chloride was dropped thereinto and the resulting mixture washeated under reflux for 1 hour. The reaction mixture was concentratedand aqueous ammonia was added thereto. Then it was extracted with ethylacetate, washed with a saturated aqueous solution of sodium chloride anddried over anhydrous magnesium sulfate. After concentrating underreduced pressure, 0.7 g of the title compound was obtained as a palebrown oily substance.

¹H-NMR(CDCl₃) δ ppm; 1.28(t, J=5 Hz, 3H), 1.25-1.70(m, 6H), 1.70-1.85(m,4H), 2.13(s, 3H), 2.05-2.25(m, 2H), 2.25-2.50(m, 1H), 2.80-3.00(m, 2H),3.55(t, J=5 Hz, 2H), 4.05(s, 2H), 4.21(q, J=5 Hz, 2H)

Production Example 70 Ethyl(anti)-(3-methyl-(syn)-9-methoxy-3-azabicyclo[3.3.1]non-9-yl)acetate andethyl(syn)-(3-methyl-(anti)-9-methoxy-3-azabicyclo[3.3.1]non-9-yl)acetate

To a solution of 2.5 ml of ethyl acetate in dry tetrahydrofuran (100 ml)was added at −78° C. 27.5 ml of a 1.0 M solution of lithiumbis(trimethylsilyl)amide in hexane and the resulting mixture was stirredfor 1 hour. Next, 3.0 g of 3-methyl-3-azabicyclo[3.3.1]nonan-9-one wasdropped thereinto and the mixture was slowly heated from −78° C. to roomtemperature and reacted for 3 hours. After adding a cold saturatedaqueous solution of ammonium chloride, the reaction mixture wasextracted with ethyl acetate. The extract was washed with a saturatedaqueous solution of sodium chloride, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure to thereby give 5.3 g ofa yellow oily substance.

To a solution of 1.0 g of this oily substance and 0.34 ml of methyliodide in dry N,N-dimethylformamide (20 ml) was added sodium hydride(oily: 60% or above) at room temperature and the mixture was reacted for12 hours. After adding ice/water, the reaction mixture was extractedwith ethyl acetate, washed with a saturated aqueous solution of sodiumchloride and dried over anhydrous magnesium sulfate. After concentratingunder reduced pressure, the residue was purified by silica gel columnchromatography (eluted with n-hexane/ethyl acetate) to thereby give 0.3g (anti) and 0.1 g (syn) of the title compounds each as a yellow oilysubstance.

¹H-NMR(CDCl₃) δ ppm;

Anti

1.24(t, J=5 Hz, 3H), 1.30-1.45(m, 1H), 1.45-1.55(m, 2H), 1.55-1.65(m,1H), 1.9-2.11(m, 3H), 2.19(s, 3H), 2.3-2.5(m, 1H), 2.50(br.d, J=13 Hz,2H), 2.76(s, 2H), 2.84(br.d, J=13 Hz, 2H), 3.28(s, 3H), 4.13(q, J=5 Hz,2H)

Syn

1.25(t, J=5 Hz, 3H), 1.35-1.50(m, 1H), 1.55(br.s, 2H), 1.74-1.90(m, 4H),1.98(br.s, 2H), 2.13(br.s, 2H), 2.58(br.s, 3H), 2.4-2.6(m-1H), 2.76(s,2H), 3.25(s, 3H), 4.14(q, J=5 Hz, 2H)

Production Example 713-(tert-Butoxycarbonyl)-3-azabicyclo[3.3.1]nonane-9-spiro-(3′-methylene)cyclobutane

7 g of the title compound was obtained as a colorless oily substancefrom 9.7 g of3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.1]nonane-9-spiro-cyclobutan-3′-oneby the same method as the one of Production Example 14.

¹H-NMR(CDCl₃) δ ppm; 1.46(s, 9H), 1.3-1.8(m, 8H), 2.52(s, 2H), 2.56(s,2H), 3.03(d, J=12 Hz, 1H), 3.11(d, J=12 Hz, 1H), 3.88(d, J=13 Hz, 1H),4.01(d, J=13 Hz, 1H), 4.81(m, 2H)

Production Example 72[3-(tert-Butoxycarbonyl)-3-azabicyclo[3.3.1]nonane-9-spiro-cyclobut-3′-yl]methanol

To a solution of 5 g of3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.1]nonane-9-spiro-(3′-methylene)cyclobutanein dry tetrahydrofuran (100 ml) was added 106 ml of a 1 M solution of aborane/tetrahydrofuran complex in tetrahydrofuran at 0° C. and theresulting mixture was reacted f or 12 hours. After adding 33 ml of 4 Nsodium hydroxide at 0° C., 49 ml of a 30% aqueous solution of hydrogenperoxide was further added thereto and the resulting mixture was stirredat room temperature for 3 hours. After adding an aqueous solution ofsodium thiosulfate, the reaction mixture was extracted with ethylacetate, washed with a saturated aqueous solution of sodium chloride anddried over anhydrous magnesium sulfate. After concentrating, the residuewas purified by silica gel column chromatography (eluted with ethylacetate/n-hexane) to thereby give 4.7 g of the title compound as acolorless oil.

¹H-NMR(CDCl₃) δ ppm; 1.3-1.9(m, 10H), 1.45(s, 9H), 2.0-2.18(m, 2H),2.28-2.44(m, 1H), 2.94-3.2(m, 2H), 3.58(d, J=6 Hz, 2H), 3.64(t, J=6 Hz,1H), 3.83(br.t, J=15 Hz, 1H), 3.96(br.t, J=13 Hz, 1H)

Production Example 73[3-(tert-Butoxycarbonyl)-3-azabicyclo[3.3.1]nonane-9-spiro-cyclobut-3′-yl]carbaldehyde

Into a solution of 1.6 ml of oxalyl chloride in methylene chloride (50ml) was dropped 1.4 ml of dry dimethyl sulfoxide at −78° C. Next, asolution of 4.6 g of[3-(tert-butoxy-carbonyl)-3-azabicyclo[3.3.1]nonane-9-spiro-cyclobut-³′-yl]-methanolin methylene chloride (20 ml) was added thereto. After reacting at −78°C. for 40 minutes, 8.7 ml of triethylamine was dropped thereinto. Thenthe reaction mixture was stirred from −78° C. to room temperature over30 minutes. After adding water, the reaction mixture was extracted withethyl acetate, washed with a saturated aqueous solution of sodiumchloride and dried over anhydrous magnesium sulfate. After concentratingunder reduced pressure, the residue was purified by silica gel columnchromatography (eluted with ethyl acetate/n-hexane) to thereby give 3.4g of the title compound as a pale yellow oily substance.

¹H-NMR(CDCl₃) δ ppm; 1.37((br.s, 1H), 1.4-1.85(m, 7H), 1.45(s, 9H),2.0-2.25(m, 4H), 2.95-3.20(m, 2H), 3.83(d, J=13 Hz, 1H), 3.88(d, J=13Hz, 1H), 3.99(t, J=14 Hz, 1H), 9.75(s, 1H)

Production Example 74 Methyl[3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.1]nonane-9-spiro-cyclobut-3′-yl]carboxylate

To a solution of 3.4 g of[3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.1]nonane-9-spiro-cyclobut-3′-yl]carbaldehydein methanol (17 ml) was added 15.4 g of sodium hydrogencarbonate. Then 2ml of bromine was dropped thereinto. After reacting at room temperaturefor 1 hour, ice/water and an aqueous solution of sodium thiosulfate wereadded thereto followed by the extraction with ethyl acetate. The extractwas washed with a saturated aqueous solution of sodium chloride, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (eluted with ethyl acetate/n-hexane) to thereby give 1.4g of the title compound as a colorless oily substance.

¹H-NMR(CDCl₃) δ ppm;

1.1-1.2(m, 1H), 1.45(s, 9H), 1.5-1.8(m, 8H), 2.00-2.15(m, 2H),2.15-2.33(m, 2H), 2.93-3.05(m, 1H), 3.08(br.d, J=13 Hz, 1H), 3.68(s,3H), 3.85(br.t, J=11 Hz, 1H), 3.99(br.t, J=11 Hz, 1H)

Production Example 75N-Allyl-N-methyl-6-methoxycarbonyl-2-oxa-3-oxobicyclo[2.2.2]oct-5-ene-7-carboxamideandN-allyl-N-methyl-6-methoxycarbonyl-2-oxa-3-oxobicyclo[2.2.2]oct-5-ene-8-carboxamide

A mixture of 10.42 g of methyl coumalate with 10.56 g ofN-allyl-N-methylacrylamide was stirred at 100° C. for 17 hours. Then thereaction mixture was purified by silica gel column chromatography(eluted with n-hexane/ethyl acetate) to thereby give two isomers. Fromthe less polar fraction, 7.90 g ofN-allyl-N-methyl-6-methoxycarbonyl-2-oxa-3-oxobicyclo[2.2.2]oct-5-ene-8-carboxamidewas obtained as a slightly yellow powder. From the more polar fraction,on the other hand, 4.19 g ofN-allyl-N-methyl-6-methoxycarbonyl-2-oxa-3-oxobicyclo[2.2.2]oct-5-ene-7-carboxamidewas obtained as a pale yellow oily substance.

¹H-NMR(CDCl₃) δ ppm; 1.81, 1.90(m, total 1H), 2.28, 2.34(m, total 1H),2.88, 3.05(s, total 3H), 3.49, 3.57(m, total 1H), 3.65-3.72(m, 1H),3.82, 3.84(s, total 3H), 3.96-4.07(m, 2H), 5.12-5.32(m, 2H),5.56-5.86(m, 2H), 7.32-7.38(m, 1H)

¹H-NMR(CDCl₃) δ ppm; 1.74, 1.77(d, J=5.1 Hz, total 1H), 2.66, 2.75(ddd,J=4.2, 6.4, 10.4 Hz, total 1H), 2.89, 2.97(s, total 3H), 3.23, 3.31(m,total 1H), 3,79(s, 3H), 3.82-4.00(m, 3H), 5.10-5.30(m, 2H), 5.64-5.81(m,2H), 7.51, 7.53(d, J=2.2 Hz, total 1H)

Production Example 76 Methyl3-methyl-2-oxo-3-azatricyclo[5.3.1.0^(5,10)]undec-8-ene-9-carboxylate

4.75 g ofN-allyl-N-methyl-6-methoxycarbonyl-2-oxa-3-oxobicyclo[2.2.2]oct-5-ene-7-carboxamidewas stirred at 180° C. for 6 hours. Then the reaction mixture waspurified by silica gel column chromatography (eluted with n-hexane/ethylacetate) to thereby give 0.93 g of the title compound as a pale yellowoily substance.

¹H-NMR(CDCl₃) δ ppm; 1.33(ddd, J=2.0, 5.3, 12.6 Hz, 1H), 1.57(dt, J=3.1,13.2 Hz, 1H), 1.69-1.84(m, 2H), 1.90(m, 1H), 2.38(m, 1H), 2.79(m, 1H),2.98(br.s, 3H), 3.17(dd, J=1.5, 12.3 Hz, 1H), 3.32(m, 1H), 3.53(dd,J=4.4, 12.3 Hz, 1H), 3.77(s, 3H), 7.44(dd, J=1.5, 7.0 Hz, 1H)

Production Example 77 Methyl3-methyl-2-oxo-3-azatricyclo[5.3.1.0^(5,10)]undec-8-ene-8-carboxylate

The title compound was obtained as a pale yellow oily substance fromN-allyl-N-methyl-6-methoxycarbonyl-2-oxa-3-oxobicyclo[2.2.2]oct-5-ene-8-carboxamideby the same method as the one of Production Example 76.

¹H-NMR(CDCl₃) δ ppm; 1.34(ddd, J=2.0, 5.1, 12.8 Hz, 1H), 1.59(dt, J=3.1,13.2 Hz, 1H), 1.71-1.94(m, 3H), 2.38(m, 1H), 2.86(m, 1H), 2.98(s, 3H),3.18-3.25(m, 2H), 3.49(dd, J=4.2, 12.3 Hz, 1H), 3.77(s, 3H), 7.29(dd,J=1.6, 7.0 Hz, 1H)

Production Example 78 Methyl3-methyl-2-oxo-3-azatricyclo[5.3.1.0^(5,10)]undecane-9-carboxylate

0.7 g of methyl 3-methyl-2-oxo-3-azatricyclo-[5.3.10^(5,10)]undec-8-ene-9-carboxylate was dissolved in methanol (15 ml).After adding 0.3 g of 10% palladium-carbon, the resulting mixture washydrogenated at ordinary temperature under atmospheric pressure for 19hours. After filtering off the catalyst, the residue was concentratedunder reduced pressure. After adding ethyl acetate to the residue, itwas filtered and the filtrate was concentrated under reduced pressure tothereby give 0.78 g of the title compound as a slightly yellow oilysubstance.

¹H-NMR(CDCl₃) δ ppm; 1.30(m, 1H), 1.46(m, 1H), 1.59(m, 1H), 1.76-2.14(m,5H), 2.17(m, 1H), 2.54(m, 1H), 2.71(m, 1H), 2.94(br.s, 3H), 3.03(dd,J=1.6, 12.1 Hz, 1H), 3.47(dd, J=1.6, 12.1 Hz, 1H), 3.68(s, 3H)

Production Example 79 Methyl3-methyl-2-oxo-3-azatricyclo[5.3.1.0^(5,10)]undecane-8-carboxylate

The title compound was obtained as a slightly yellow oily substance frommethyl3-methyl-2-oxo-3-azatricyclo-[5.3.1.0^(5,10)]undec-8-ene-8-carboxylateby the same method as the one of Production Example 78.

¹H-NMR(CDCl₃) δ ppm; 1.36(m, 1H), 1.44(m, 1H), 1.78-1.91(m, 3H),1.93-2.13(m, 4H), 2.49-2.62(m, 2H), 2.94(s, 3H), 3.02(dd, J=1.3, 11.9Hz, 1H), 3.44(dd, J=3.7, 11.9 Hz, 1H), 3.70(s, 3H)

Production Example 80 Methyl3-methyl-2-thioxo-3-azatricyclo[5.3.1.0^(5,10)]undec-8-ene-9-carboxylate

2.24 g of methyl3-methyl-2-oxo-3-azatricyclo[5.3.1.0^(5,10)]undec-8-ene-9-carboxylatewas dissolved in toluene (30 ml). After adding 2.31 g of Lawson'sreagent, the resulting mixture was heated to 100° C. for 1 hour. Thenthe reaction mixture was purified as such by silica gel columnchromatography (eluted with n-hexane/ethyl acetate) to thereby give 1.91g of the title compound as colorless needles.

¹H-NMR(CDCl₃) δ ppm; 1.31(ddd, J=2.2, 5.1, 13.0 Hz, 1H), 1.59(dt, J=3.3,13.4 Hz, 1H), 1.80(ddt, J=3.5, 11.7, 13.0 Hz, 1H), 1.98-2.08(m, 2H),2.78(m, 1H), 3.14(ddd, J=3.3, 6.0, 12.7 Hz, 1H), 3.28(m, 1H), 3.46(dd,J=1.3, 13.7 Hz, 1H), 3.49(s, 3H), 3.76(s, 3H), 3.80(ddd, J=0.4, 4.8,13.7 Hz, 1H), 7.45(dd, J=1.5, 7.0 Hz, 1H)

Production Example 81 ethyl3-methyl-3-azatricyclo5.3.1.0^(5,10)]undec-8-ene-9-carboxylate

1.0 g of methyl3-methyl-2-oxo-3-azatricyclo5.3.1.0^(5,10)]undec8-ene-9-carboxylate wasdissolved in tetrahydrofuran (32 ml). After adding 2.5 ml of methyliodide, the resulting mixture was stirred at room temperature for 19hours. After distilling off the solvent under reduced pressure, a yellowamorphous product was obtained. Then it was dissolved in methanol (26ml). After adding 0.18 g of sodium borohydrie, the resulting mixture wasstirred under ice-cooling. After 30 minutes, 0.18 g of sodiumborohydride was added thereto and the resulting mixture was stirred atroom temperature for additional 1 hour. After adding ice/water, thereaction mixture was extracted with ethyl acetate. The organic layer waswashed with water and a saturated aqueous solution of sodium chlorideand extracted with 1 N hydrochloric acid. Then aqueous ammonia was addedto the aqueous layer followed by the extraction with ethyl acetate. Theorganic layer was washed successively with water and a saturated aqueoussolution of sodium chloride and dried over anhydrous magnesium sulfate.After distilling off the solvent under reduced pressure, 0.88 g of thetitle compound was obtained as a colorless oily substance.

¹H-NMR(CDCl₃) δ ppm;

1.35-1.48(m, 2H), 1.50-1.72(m, 4H), 1.92-2.07(m, 2H), 2.28(br.s, 3H),2.61-2.80(m, 4H), 3.75(s, 3H), 7.42(dd, J=1.3, 6.8 Hz, 1H)

Production Example 82 ethyl3-methyl-3-azatricyclo[5.3.1.0^(5,10)]undecane-9-carboxylate

632 g of the title compound was obtained as a slightly yellow oilysubstance from 778 mg of3-methyl-2-oxo-3-azatricyclo[5.3.1.0^(5,10)]undecane-9-carboxylate bythe same methods as those of Production Examples 80 and 81.

¹H-NMR(CDCl₃) δ ppm; 1.46-2.06(m, 12H), 2.28(br.s, 3H), 2.50-2.70(m,3H), 3.69(s, 3H)

Production Example 83 Methyl3-methyl-3-azatricyclo[5.3.1.0^(5,10)]undecane-8-carboxylate

The title compound was obtained from3-methyl-2-oxo-3-azatricyclo[5.3.1.0^(5,10)]undecane-8-carboxylate bythe same methods as those of Production Examples 80 and 81.

¹H-NMR(CDCl₃) δ ppm; 1.21(br.s, 1H), 1.57-1.80(m, 7H), 1.84-2.14(m, 4H),2.26(br.s, 3H), 2.44-2.74(m, 3H), 3.68(s, 3H)

Examples 32 to 43

The following compounds were obtained by the same methods as those ofExamples 12, 13 and 14 optionally using potassium carbonate as a base.

TABLE 15 Ex. Structural formula NMR 32

¹H-NMR(CDCl₃) δ ppm: 1.28(t, J=7Hz, 3H), 1.47-1.65(m, 2H), 1.75-1.90(m,2H), 1.95-2.05(m, 2H), 2.07(m, 1H), 2.25-2.35(m, 3H), 2.70-2.87(m, 1H),2.98- 3.05(m, 2H), 3.95(m, 1H), 4.15(q, J=7Hz, 2H), 5.63(s, 1H), 6.44(s,1H), 6.52(d, J=1Hz, 1H), 6.79(dd, J=1, 8Hz, # 1H), 6.85(d, J=8Hz, 1H),7.58(d, J=2Hz, 1H), 7.70(d, J=2Hz, 1H) 33

¹H-NMR(CDCl₃) δ ppm: 1.4-1.9(m, total 7H), 2.20-2.28, 2.28- 2.38(m,total 2H), 2.37(m, total 1H), 2.5-2.76(m, total 1H), 2.66-2.70,2.94-3.00(m, total 2H), 3.17, 3.24(s, total 2H), 3.71, 3.72(s, total3H), 6.40(br.s, total 1H), 6.48, 6.52(m, total 1H), 6.76-6.80(m, total1H), # 6.82, 6.84(d, J=8Hz, total 1H), 7.55-7.58(m, total 1H),7.68-7.72(m, total 1H) 34

¹H-NMR(CDCl₃) δ ppm: 1.26(t, J=7Hz, 3H), 1.58(br.s, 2H), 2.10-2.18(m,1H), 2.41(d, J=11Hz, 2H), 2.65(d, J=8Hz, 2H), 3.0-3.15(m, 2H), 3.35(s,2H), 3.77(d, J=12Hz, 2H), 3.97(d, J=12Hz, 2H), 4.14(q, J=7Hz, 2H),6.75(d, J=8Hz, 1H), 6.78(s, 1H), 6.79(d, J=8Hz, 1H), # 7.14-7.18(m, 1H),7.55(d, J=3Hz, 1H), 7.65(d, J=3Hz, 1H)

TABLE 16 Ex. Structural formula NMR 35

¹H-NMR(CDCl₃) δ ppm: 0.86(d, J=6.4Hz, 3H), 1.24-1.37(m, 2H),1.60-1.70(m, 2H), 1.90-2.05(m, 2H), 2.15-2.27(m, 2H), 2.40-2.48(m, 1H),2.43(d, J=7.2Hz, 2H), 2.73-2.92(m, 3H), 3.23(s, 2H), 3.67(s, 3H),6.37(br.s, 1H), 6.46(s, 1H), 6.76(d, J=8.0Hz, 1H), 6.84(d, J=8.0Hz, 1H),7.57(d, J=7.2Hz, 1H), 7.69(d, J=7.2Hz, 1H) 36

¹H-NMR(CDCl₃) δ ppm: 0.99(s, 3H), 1.24(t, J=7.0Hz, 3H), 1.31-1.39(m,2H), 1.42(s, 3H), 1.64-1.74(m, 4H), 1.85-1.93(m, 1H), 2.12-2.19(m, 2H),2.35(d, J=7.9Hz, 2H), 2.74-2.81(m, 2H), 3.25(s, 2H), 4.12(q, J=7.0Hz,2H), 6.38- 6.43(br.s, 1H), 6.45(d, J=1.6Hz, 1H), 6.74(dd, J=1.6, #7.9Hz, 1H), 6.81(d, J=7.9Hz, 1H), 7.56(d, J=3.0Hz, 1H), 7.68(d, J=3.0Hz,1H) 37

¹H-NMR(CDCl₃) δ ppm: 1.73-1.94(m, 7H), 2.07-2.14(m, 1H), 2.30-2.38(m,2H), 2.59(d, J=7.2Hz, 2H), 2.96-3.05(m, 2H), 3.31(s, 2H), 3.69(s, 3H),6.37(br.s, 1H), 6.49(s, 1H), 6.84-6.90(m, 2H), 7.16-7.39(m, 5H), 7.57(d,J=7.2Hz, 1H), 7.69(d, J=7.2Hz, 1H)

TABLE 17 Ex. Structural formula NMR 38

¹H-NMR(CDCl₃) δ ppm: 1.06(d, J=8Hz, 3H), 1.2-1.3(m, 3H), 1.4-2.1(m, 7H),2.19(dd, J=2, 10Hz, 1H), 2.22- 2.30(m, 1H), 2.40-2.70(m, 3H),2.75-2.90(m, 2H), 3.19(d, J=14Hz, 1H), 3.26(d, J=14Hz, 1H), 4.05-4.20(m,2H), 6.36- 6.40(m, 1H), 6.50(d, J=1Hz, 1H), 6.76(dd, J=1, 8Hz, 1H), #6.82(d, J=8Hz, 1H), 7.56(d, J=3Hz, 1H), 7.69(d, J=3Hz, 1H) 39

¹H-NMR(CDCl₃) δ ppm: 0.71(s, 6H), 1.29- 1.46(m, 5H), 1.73(t, J=5.9Hz,1H), 1.90(d, J=11.8Hz, 2H), 2.33(d, J=5.9Hz, 2H), 2.63(d, J=11.8Hz, 2H),2.66-2.83(m, 1H), 3.14(s, 2H), 3.66(s, 3H), 6.48(s, 1H), 6.75(d,J=7.7Hz, 1H), 6.80(s, 1H), 6.81(d, J=7.7Hz, 1H), 7.55(d, J=2.6Hz, 1H),7.68(d, m J=2.6Hz, 1H) 40

¹H-NMR(CDCl₃) δ ppm: 1.51-1.66(m, 6Hz), 1.70-1.79(m, 3H), 1.84-2.00(m,3H), 2.51-2.63(m, 3H), 3.27(d, J=13.6Hz, 1H), 3.32(d, J=13.6Hz, 1H),3.68(s, 3H), 5.57(br.s, 1H), 6.60(br.s, 1H), 6.79(dd, J=1.5, 7.9Hz, 1H),6.82(d, J=7.9Hz, 1H), 7.57(d, J=2.9Hz, 1H), 7.69(d, J=2.9Hz, 1H)

TABLE 18 Ex. Structural formula NMR 41

¹H-NMR(CDCl₃) δ ppm: 0.75-0.90(m, 2H), 0.99(d, J=7.2Hz, 6H),1.15-1.24(m, 1H), 1.26(t, J=7.2Hz, 3H), 1.35-1.44(m, 2H), 1.72- 1.84(m,3H), 1.93(d, J=10.4Hz, 2H), 2.25-2.36(m, 1H), 2.32(t, J=7.2Hz, 2H),2.59(d, J=10.4Hz, 2H), 3.25(s, 2H), 4.12(q, J=7.2Hz, 2H), 6.38(br.s,1H), 6.51(s, 1H), 6.76(d, J=8.0Hz, 1H), # 6.82(d, J=8.0Hz, 1H), 7.57(d,J=2.8Hz, 1H), 7.69(d, J=2.8Hz, 1H) 42

¹H-NMR(CDCl₃) δ ppm: 1.23(m, 1H), 1.45(m, 1H), 1.55-1.76(m, 6H),1.89-1.96(m, 2H), 2.00-2.08(m, 2H), 2.44-2.60(m, 3H), 3.30(s, 2H),3.69(s, 3H), 6.49(br.s, 1H), 6.56(br.s, 1H), 6.80(dd, J=1.3, 8.2Hz, 1H),6.83(d, J=8.2Hz, 1H), 7.57(d, J=2.7Hz, 1H), 7.69(d, J=2.7Hz, 1H) 43

¹H-NMR(CDCl₃) δ ppm: 1.34-1.44(m, 2H), 1.56-1.65(m, 4H), 2.01-2.08(m,2H), 2.66-2.76(m, 4H), 3.35(s, 2H), 3.75(s, 3H), 6.58(br.s, 2H),6.83(br.s, 2H), 7.41(dd, J=1.3, 7.0Hz, 1H), 7.57(d, J=2.9Hz, 1H),7.69(d, J=2.9Hz, 1H)

Example 44Ethyl[8-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-8-azabicyclo[4.3.1]dec-10-yl]acetate

The title compound was obtained as a yellow oily substance by treatingethyl(8-methyl-8-azabicyclo[4.3.1]dec-10-ylidene)acetate by the samemethods as those of Examples 20, 12, 13 and 14 by using potassiumcarbonate as a base.

¹H-NMR(CDCl₃) δ ppm; 1.25(t, J=7.0 Hz, 3H), 1.50-1.62(m, 4H),1.75-1.87(m, 2H), 1.87-1.95(m, 2H), 1.97-2.10(m, 4H), 2.17-2.26(m, 1H),2.50(d, J=7.3 Hz, 2H), 2.62-2.68(m, 2H), 3.20(s, 2H), 4.12(q, J=7.0 Hz,2H), 6.42-6.47(br.s, 1H), 6.51(d, J=1.5 Hz, 1H), 6.78(dd, J=1.5, 7.8 Hz,1H), 6.82(d, J=7.8 Hz, 1H), 7.56(d, J=3.1 Hz, 1H), 7.68(d, J=3.1 Hz, 1H)

Examples 45 to 47

The following compounds were obtained by the same methods as those ofExamples 13 and 14 by using potassium carbonate as a base.

TABLE 19 Ex. Structural formula NMR 45

¹H-NMR(CDCl₃) δ ppm: 1.10(d, J=7Hz, 3H), 1.24(t, J=7Hz, 3H),1.52-1.90(m, 9H), 2.29(br.d, J=12Hz, 1H), 2.49(br.d, J=12Hz, 2H),2.63(br.d, J=12Hz, 1H), 2.80(dd, J=8, 12Hz, 1H), 3.23(s, 2H), 4.13(q,J=7Hz, 2H), 6.38(br.s, 1H), 6.50(d, J=2Hz, 1H), 6.76(dd, J=2, 8Hz, 1H),6.82(d, J=8Hz, 1H), 7.56(d, J=3Hz, 1H), 7.69(d, J=3Hz, 1H) 46

¹H-NMR(CDCl₃) δ ppm: 1.11(d, J=7Hz, 3H), 1.24(t, J=7Hz, 3H),1.46-1.55(m, 4H), 1.56-1.64(s, 2H), 1.77(br.s, 1H), 1.82-1.95(m, 1H),2.20(m, 2H), 2.55(m, 1H), 2.82(dd, J=7, 11Hz, 1H), 2.88(br.d, J=11Hz,1H), 2.96(br.d, J=11Hz, 1H), 3.21(s, 2H), 4.12(q, J=7Hz, 2H), 6.43(br.s,1H), 6.50(d, J=2Hz, 1H), 6.77(dd, J=2, # 8Hz, 1H), 6.82(d, J=8Hz, 1H),7.56(d, J=3Hz, 1H), 7.68(d, J=3Hz, 1H) 47

¹H-NMR(CDCl₃) δ ppm: 1.01(d, J=7.1Hz, 3H), 1.09(d, J=7.0Hz, 3H), 1.25(t,J=7.1Hz, 3H), 1.49-1.59(m, 2H), 1.64(m, 1H), 1.74(m, 1H), 2.22(m, 1H),2.27(d, J=10.0Hz, 1H), 2.36(d, J=12.5Hz, 1H), 2.39(dd, J=3.9, 11.2Hz,1H), 2.48(dd, J=7.1, 15.0Hz, 1H), 2.53-2.60(m, 2H), 3.28(d, # J=13.2Hz,1H), 3.38(d, J=13.2Hz, 1H), 4.13(q, J=7.1Hz, 2H), 6.49(d, J=1.3Hz, 1H),6.50(br.s, 1H), 6.76(dd, J=1.3, 7.9Hz, 1H), 6.81(d, J=7.9Hz, 1H),7.57(d, J=2.9Hz, 1H), 7.69(d, J=2.9Hz, 1H)

Examples 48 to 59

The following compounds were obtained by the same method as the one ofExample 17.

TABLE 20 Ex. Structural formula NMR 48

¹H-NMR(CDCl₃) δ ppm: 1.25(t, J=7Hz, 3H, anti), 1.26(t, J=7Hz, 3H, syn),1.5-2.1(m, 7H), 2.08-2.15(m, 2H, anti), 2.16(d, J=8Hz, 2H, anti),2.35-2.45(m, 4H, syn), 2.58(d, J=7Hz, 2H, syn), 2.62-2.70(m, 2H, anti),3.31(s, 2H, anti), 3.34(s, 2H, syn), 4.13(q, J=7Hz, 2H, anti), 4.14(q,J=7Hz, 2H, # syn), 6.42(br.s, 1H), 6.53(br.s, 1H), 6.77(d, J=8Hz, 1H),6.82(d, J=8Hz, 1H), 7.57(d, J=3Hz, 1H), 7.69(d, J=3Hz, 1H) 49

¹H-NMR(CDCl₃) δ ppm: 1.28(t, J=7Hz, 3H), 1.50-1.75(m, 2H), 1.8- 2.0(m,2H), 2.21(d, J=10Hz, 1H), 2.29(d, J=10Hz, 1H), 2.47(m, 1H), 2.83(dd,J=4, 10Hz, 2H), 3.31(d, J=16Hz, 1H), 3.37(d, J=16Hz, 1H), 3.75(m, 1H),4.16(q, J=7Hz, 2H), 5.63(s, H), 6.46- 6.56(m, 1H), 6.54(s, 1H), 6.78(d,J=8Hz, 1H), 6.83(d, # J=8Hz, 7.58(d, J=3Hz, 1H), 7.70(d, J=3Hz, 1H) 50

¹H-NMR(CDCl₃) δ ppm: 1.70(m, 4H), 2.10(d, J=10Hz, 2H), 2.34(s, 1H),2.50(br.s, 2H), 2.71(dd, J=4, 10Hz, 2H), 3.33(s, 2H), 3.66(s, 3H),6.44(br.s, 1H), 6.53(d, J=1Hz, 1H), 6.77(dd, J=1, 8Hz, 1H), 6.83(d,J=8Hz, 1H), 7.57(d, J=3Hz, 1H), 7.69(d, J=3Hz, 1H)

TABLE 21 Ex. Structural formula NMR 51

¹H-NMR(CDCl₃) δ ppm: 0.89(s, 9H), 1.24-1.36(m, 3H), 1.76- 1.92(m, 5H),2.01-2.06(m, 2H), 2.50(d, J=7.2Hz, 2H), 2.56- 2.63(m, 2H), 3.23(s, 2H),3.68(s, 3H), 6.22(br.s, 1H), 6.52(s, 1H), 6.78(d, J=8.0Hz, 1H), 6.82(d,J=8.0Hz, 1H), 7.57(d, J=2.8Hz, 1H), 7.69(d, J=2.8Hz, 1H) 52

¹H-NMR(CDCl₃) δ ppm: 0.80-1.00(m, 1H), 0.99(d, J=6.8Hz, 6H),1.40-1.45(m, 2H), 1.68-1.90(m, 4H), 2.03(d, J=10Hz, 2H), 2.46(d,J=7.6Hz, 2H), 2.58(d, J=10Hz, 2H), 3.26(s, 2H), 3.67(s, 3H), 6.38(br.s,1H), 6.51(s, 1H), 6.76(d, J=8.0Hz, 1H), 6.82(d, J=8.0Hz, 1H), 7.56(d,J=2.8Hz, 1H), 7.69(d, J=2.8Hz, 1H) 53

¹H-NMR(CDCl₃) δ ppm: 1.23(t, J=7.1Hz, 3H), 1.54-1.82(m, 6H), 1.88-1.98(m, 2H), 2.13(m, 1H), 2.13(m, 1H), 2.20(dd, J=2.0, 10.8Hz, 1H),2.70(m, 1H), 2.81(m, 1H), 3.06(m, 1H), 3.21(d, J=13.4Hz, 1H), 3.27(d,J=13.4Hz, 1H), 4.09(q, J=7.1Hz, 2H), 6.43(br.s, 1H), 6.49(d, J=1.3Hz,1H), 6.77(dd, J=1.3, 7.9Hz, 1H), 6.84(d, # J=7.9Hz, 1H), 7.57(d,J=2.9Hz, 1H), 7.69(d, J=2.9Hz, 1H)

TABLE 22 Ex. Structural formula NMR 54

¹H-NMR(CDCl₃) δ ppm: 1.28(t, J=7Hz, 3H), 1.4-1.55(m, 2H), 1.56-1.65(m,3H), 1.7-1.85(m, 5H), 2.22(br.d, J=11Hz, 2H), 2.45-2.6(m, 1H), 2.91(d,J=11Hz, 2H), 3.21(s, 2H), 3.55(t, J=7Hz, 2H), 4.06(s, 2H), 4.21(q,J=7Hz, 2H), 6.40(br.s, 1H), 6.51(s, 1H), 6.77(d, J=8Hz, 1H), 6.82(d,J=8Hz, 1H), 7.56(d, J=3Hz, 1H), # 7.68(d, J=3Hz, 1H) 55

¹H-NMR(CDCl₃) δ ppm: 1.45-1.55(m, 2H), 1.62-1.75(m, 4H), 1.75-1.90(m,2H), 1.96(q, J=7Hz, 2H), 2.20-2.25(m, 2H), 2.50-2.63(m, 1H),2.90-2.95(m, 2H), 3.22(s, 2H), 3.56(s, 2H), 3.68(s, 3H), 3.97(t, J=6Hz,2H), 6.46-6.50(m, 1H), 6.51(d, J=1Hz, 1H), 6.78(dd, J=1, 8Hz, 1H),6.83(d, J=8Hz, 1H), 6.85(d, # J=8Hz, 2H), 7.18(d, J=8Hz, 2H), 7.56(d,J=3Hz, 1H), 7.68(d, J=3Hz, 1H) 56

¹H-NMR(CDCl₃) δ ppm: 1.24(t, J=7Hz, 3H), 1.44-1.54(m, 2H), 1.59(d,J=5Hz, 1H), 1.9-2.3(m, 4H), 2.53(br.d, J=12Hz, 3H), 2.77(s, 2H),2.85(br.d, J=12Hz, 2H), 3.28(s, 3H), 3.29(s, 2H), 4.13(q, J=7Hz, 2H),6.42(m, 1H), 6.49(d, J=1Hz, 1H), 6.76(dd, J=1, 8Hz, 1H), 6.83(d, J=8Hz,1H), 7.57(d, # J=3Hz, 1H), 7.67(d, J=3Hz, 1H)

TABLE 23 Ex. Structural formula NMR 57

¹H-NMR(CDCl₃) δ ppm: 1.22(t, J=7.1Hz, 3H), 1.36-1.61(m, 5H),1.66-1.78(m, 2H), 1.88-1.97(m, 2H), 2.06(s, 2H), 2.10(m, 1H), 2.69(m,1H), 2.78- 2.88(m, 2H), 3.17(d, J=13.6Hz, 1H), 3.23(d, J=13.6Hz, 1H),4.10(q, J=7.1Hz, 2H), 6.42(br.s, 1H), 6.49(d, J=1.6Hz, 1H), 6.76(dd,J=1.6, 7.9Hz, 1H), 6.83(d, J=7.9Hz, 1H), 7.57(d, J=2.9Hz, # 1H), 7.69(d,J=2.9Hz, 1H) 58

¹H-NMR(CDCl₃) δ ppm: 1.25(t, J=7Hz, 3H), 1.45-1.55(m, 1H), 1.72-1.80(m,2H), 1.80-1.95(m, 2H), 1.99(br.s, 2H), 2.3-2.35(m, 1H), 2.5-2.65(m, 4H),2.77(s, 2H), 3.22(s, 2H), 3.20(s, 3H), 4.14(q, J=7Hz, 2H), 6.40(s, 1H),6.49(d, J=1Hz, 1H), 6.77(dd, J=1, 8Hz, 1H), 6.82(d, J=8Hz, 1H), 7.56(d,J=3Hz, 1H), 7.68(d, J=3Hz, 1H) 59

¹H-NMR(CDCl₃) δ ppm: 1.2-2.2(m, 10H), 2.23(br.d, J=10Hz, 2H), 2.4-2.6(m,1H), 2.94(br.d, J=10Hz, 2H), 3.21(s, 2H), 3.90(s, 3H), 4.03(t, J=5Hz,2H), 6.35(s, 1H), 6.51(s, 1H), 6.78(d, J=7Hz, 1H), 6.84(d, J=7Hz, 1H),7.0-7.1(m, 1H), 7.3-7.4(m, 1H), 7.5-7.8(m, 4H)

Example 60 Ethyl(anti)-(6R*,8R*)-4-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-6,8-dimethyl-3-azabicyclo[3.3.1]non-9-yl]butanoate

To a solution of 1.0 g ofethyl(6R*,8R*)-4-[3-(vinyloxycarbonyl)-6,8-dimethyl-3-azabicyclo[3.3.1]non-9-yl]-2-butenoatein dioxane (10 ml) was added 30 ml of a 4 N solution of hydrochloricacid in dioxane and the resulting mixture was stirred at roomtemperature. After distilling off the solvent under reduced pressure, 10ml of methanol was added to the residue and the resulting mixture washeated under reflux for 1 hour. After distilling off the solvent underreduced pressure, the residue was made alkaline by adding a diluteaqueous solution of sodium hydroxide and extracted with ethyl acetate.The organic layer was dried over anhydrous magnesium sulfate. Afterdistilling off the solvent under reduced pressure, 0.25 g of 10%palladium-carbon (moisture content: 50%) was added to the residualmethanolic solution and the resulting mixture was stirred under ahydrogen gas stream at room temperature overnight. Then the reactionmixture was filtered through celite. After distilling off the solventunder reduced pressure, 0.9 g of a pale yellow oily substance wasobtained.

To a solution of 0.9 g of this yellow oily substance and 0.75 g of8-chloromethyl-10H-pyrazino[2,3-b][1,4]benzothiazine inN,N-dimethylformamide was added 1.24 g of potassium carbonate and theresulting mixture was stirred at 100° C. for 3 hours. After adding ethylacetate, the reaction mixture was washed with a saturated aqueoussolution of sodium chloride. Then the organic layer was dried overanhydrous magnesium sulfate. After distilling off the solvent underreduced pressure, the residue was purified by silica gel columnchromatography (eluted with n-hexane/ethyl acetate) to thereby give 1.0g of the title compound as a yellow oily substance.

H-NMR(CDCl₃) δ ppm; 0.98(d, J=7.2 Hz, 6H), 1.18-1.80(m, 13H), 1.93(d,J=9.2 Hz, 2H), 2.28(t, J=7.2 Hz, 2H), 2.58(d, J=9.2 Hz, 2H), 3.02(d,J=9.2 Hz, 1H), 3.25(s, 2H), 4.13(q, J=7.2 Hz, 2H), 6.43(br.s, 1H),6.52(s, 1H), 6.76(d, J=8.0 Hz, 1H), 6.82(d, J=8.0 Hz, 1H), 7.56(d, J=2.8Hz, 1H), 7.68(d, J=2.8 Hz, 1H)

Examples 61 and 62

The following compounds were obtained by the same method as the one ofExample 60.

TABLE 24 Ex. Structural formula NMR 61

¹H-NMR(CDCl₃) δppm: 1.16(d, J=7.0Hz, 3H), 1.26(d, J=7.1Hz, 3H),1.32-1.68(m, 10H), 1.68-1.83(m, 2H), 2.15-2.22(m, 2H), 2.41(m, 1H),2.52(m, 1H), 2.88-2.95(m, 2H), 3.21(s, 2H), 4.14(q, J=7.1Hz, 2H),6.38(br.s, 1H), # 6.52(d, J=1.5Hz, 1H), 6.78(dd, J=1.5, 7.9Hz, 1H),6.83(d, J=7.9Hz, 1H), 7.57(d, J=2.9Hz, 1H), 7.69(d, J=2.9Hz, 1H) 62

¹H-NMR(CDCl₃) δppm: 0.97(d, J=6.8Hz, 6H), 1.14(d, J=6.8Hz, 3H), 1.26(t,J=7.2Hz, 3H), 1.30-1.80(m, 11H), 1.93(d, J=12.4Hz, 2H), 2.34-2.45(m,1H), 2.58(d, J=12.4Hz, 2H), 3.24(s, 2H), 4.12(d, J=7.2Hz, 2H),6.36(br.s, 1H), # 6.52(s, 1H), 6.76(d, J=8.0Hz, 1H), 6.81(d, J=8.0Hz,1H), 7.57(d, J=2.8Hz, 1H), 7.68.(d, J=2.8Hz, 1H)

Example 63 Methyl(anti)-3-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]non-9-yl]propanoate

The title compound was obtained by treating methyl(anti)-3-(3-azabicyclo[3.3.1]non-9-yl)propanoate by the same method asthe one of Example 14 by using potassium carbonate as a base.

¹H-NMR(CDCl₃) δ ppm; 1.37-1.55(m, 4H), 1.58-1.90(m, 6H), 2.16-2.23(m,2H), 2.30(t, J=7.2 Hz, 2H), 2.53(m, 1H), 2.88-2.96(m, 2H), 3.22(s, 2H),3.68(s, 3H), 6.37(br.s, 1H), 6.51(d, J=1.3 Hz, 1H), 6.77(dd, J=1.3, 7.9Hz, 1H), 6.83(d, J=7.9 Hz, 1H), 7.57(d, J=2.9 Hz, 1H), 7.69(d, J=2.9 Hz,1H)

Example 64 Methyl(syn)-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]non-7-yl]carboxylate

360 mg of methyl (syn)-[3-benzyl-3-azabicyclo[3.3.1]non-7-yl]carboxylatewas dissolved in methanol (15 ml). After adding 0.5 g of 10%palladium-carbon and 0.3 ml of conc. hydrochloric acid, the resultingmixture was hydrogenated at 60° C. under atmospheric pressure for 2hours. After filtering off the catalyst, the residue was concentratedunder reduced pressure to thereby give a slightly yellow oily substance.

This oily substance was dissolved in 5 ml of N,N-dimethylformamide.After adding 320 mg of8-chloromethyl-10H-pyrazino[2,3-b][1,4]benzothiazine and 0.68 ml ofN,N-diisopropylethylamine, the resulting mixture was stirred at 80° C.for 3 hours. After adding water, the reaction mixture was extracted withethyl acetate. The ethyl acetate layer was washed with water and asaturated aqueous solution of sodium chloride, dried over anhydroussodium sulfate and concentrated under reduced pressure. Next, theresidue was purified by silica gel column chromatography (eluted withn-hexane/ethyl acetate) to thereby give 111 mg of the title compound asa yellow solid.

¹H-NMR(CDCl₃) δ ppm; 1.31(m, 1H), 1.51(m, 1H), 1.74-1.88(m, 4H),2.16-2.26(m, 2H), 2.37-2.47(m, 2H), 2.53(m, 1H), 2.65-2.74(m, 2H),3.30(s, 2H), 3.72(s, 3H), 6.48(br.s, 1H), 6.62(d, J=7.9 Hz, 1H),6.63(br.s, 1H), 6.81(d, J=7.9 Hz, 1H), 7.53(d, J=2.9 Hz, 1H), 7.68(d,J=2.9 Hz, 1H)

Example 65

The following compound was obtained by the same method as the one ofExample 64.

TABLE 25 Ex. Structural formula NMR 65

¹H-NMR(CDCl₃) δppm: 1.05(m, 1H), 1.28(t, J=7.1Hz, 3H), 1.35- 1.46(m,2H), 1.72- 1.80(m, 2H), 1.85- 2.08(m, 6H), 2.33(d, J=6.0Hz, 2H), 2.50-2.57(m, 2H), 3.28(s, 2H), 4.18(q, J=7.1Hz, 2H), 6.70(d, J=7.9Hz, # 1H),6.79(d, J=7.9Hz, 1H), 6.81(s, 1H), 7.19(br.s, 1H), 7.56(d, J=2.9Hz, 1H),7.65(d, J=2.9Hz, 1H)

Example 66Ethyl[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]nonane-9-spiro-cyclobut-3′-yl]acetate

To a solution of 4.7 g ofethyl[3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.1]nonane-9-spiro-cyclobut-3′-yl]acetatein tetrahydrofuran (50 ml) was added 20 ml of conc. hydrochloric acidand the resulting mixture was stirred at room temperature for 1 hour.After concentrating the reaction mixture under reduced pressure, 3.7 gof crude ethyl(3-azabicyclo[3.3.1]nonane-9-spiro-cyclobut-3′-yl)acetatewas obtained. To a solution of 2.0 g of this crude product inN,N-dimethylformamide (30 ml) were added 1.3 g of8-chloromethyl-10H-pyrazino[2,3-b][1,4]benzothiazine and 3 g ofanhydrous potassium carbonate and the resulting mixture was stirred at100° C. for 3 hours. Then the reaction mixture was brought back to roomtemperature and ice/water was added thereto followed by the extractionwith ethyl acetate. Next, it was washed with a saturated aqueoussolution of sodium chloride and dried over anhydrous magnesium sulfate.After distilling off the solvent under reduced pressure, the residue waspurified by silica gel column chromatography (eluted with ethylacetate/toluene) to thereby give 1.0 g of the title compound as a yellowoily substance.

¹H-NMR(CDCl₃) δ ppm; 1.18(t, J=7 Hz, 3H), 1.2-1.90(m, 10H), 2.1-2.6(m,7H), 2.29(d, J=12 Hz), 3.08(s, 2H), 4.04(q, J=2 Hz, 2H), 6.3-6.45(m,1H), 6.43(d, J=2 Hz, 1H), 6.69(dd, J=2, 8 Hz, 1H), 6.75(d, J=8 Hz, 1H),7.49(d, J=3 Hz, 1H), 7.62(d, J=3 Hz, 1H)

Examples 67 and 68

The following compounds were obtained by the same method as the one ofExample 66.

TABLE 26 Ex. Structural formula NMR 67

¹H-NMR(CDCl₃) δppm: 0.70(q, J=10Hz, 1H), 0.99(d, J=7Hz, 3H), 1.04(d,J=7Hz, 3H), 1.24(t, J=7Hz, 3H), 1.4-1.55(m, 3H), 1.6- 1.7(m, 2H),1.7-1.9(m, 2H), 1.98(d, J=10Hz, 1H), 2.10(d, J=10Hz, 1H), 2.15-2.25(m,2H), 2.25-2.4(m, 2H), # 2.36(d, J=8Hz, 2H), 2.45-2.6(m, 1H), 3.18(s,2H), 4.10(q, J=7Hz, 2H), 6.49(s, 1H), 6.6-6.7(br.s, 1H), 6.74(d, J=8Hz,1H), 6.80(d, J=8Hz, 1H), 7.56(d, J=3Hz, 1H), 7.66-7.69(m, 1H) 68

¹H-NMR(CDCl₃) δppm: 1.3-1.4(m, 1H), 1.5- 1.64(m, 5H), 1.7- 1.86(m, 1H),1.96- 2.14(m, 2H), 2.12- 2.38(m, 3H), 2.29(br.d, J=12Hz, 1H), 2.44-2.60(m, 1H), 2.66(t, J=13Hz, 2H), 2.92(quint, J=9Hz, 1H), 3.13(d,J=14Hz, 1H), # 3.17(d, J=14Hz, 1H), 3.67(s, 3H), 6.49(s, 1H), 6.53(s,1H), 6.75(d, J=8Hz, 1H), 6.81(d, J=8Hz, 1H), 7.56(d, J=3Hz, 1H), 7.68(d,J=3Hz, 1H)

Example 69 Ethyl(anti)-[[3-(10H-pyrazino[2,3-b][1,4benzothiazin-8-ylmethyl)-3-azabicyclo[3.1.1]heptane-7-spiro-cyclobutan]-6-yl]acetateand ethyl(syn)-[[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.1.1]heptane-7-spiro-cyclobutan]-6-yl]acetate

In a nitrogen atmosphere, 2.00 g of ethyl[[3-(p-tolylsulfonyl)-3-azabicyclo[3.3.1]heptane-7-spiro-cyclobutan]-6-yl]acetatewas dissolved in 90 ml of dry 1,2-dimethoxyethane and the obtainedsolution was cooled to −70° C. Into the above sulfonamide solution wasdropped in a nitrogen atmosphere a green solution of sodiumnaphthalenide obtained by reacting 6.8 g of naphthalene with 0.97 g ofsodium in 100 ml of dimethoxyethane. After adding 5 ml of an aqueoussolution of sodium hydrogencarbonate, 6 g of anhydrous sodium carbonateand 150 ml of ethyl acetate, the organic layer was dried over potassiumcarbonate and distilled off under reduced pressure. To a solution of thecrude product thus obtained in 35 ml of N,N-dimethylformamide were added1.99 g 8-chloromethyl-10H-pyrazino[2,3-b][1,4]benzothiazine and 0.89 gof anhydrous potassium hydrogencarbonate and the resulting mixture wasreacted at 90° C. in a nitrogen atmosphere for 2 hours. Then thereaction mixture was cooled to room temperature and added to 350 ml ofwater and 350 ml of ethyl acetate. The organic layer was washed withwater, dried over anhydrous magnesium sulfate, filtered and distilledunder reduced pressure. The residue was purified by silica gel columnchromatography (eluted with methylene chloride/methanol) to thereby give0.62 g of ethyl(anti)-[[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.1.1]heptane-7-spiro-cyclobutan]-6-yl]acetateand 0.49 g of ethyl(syn)-[[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.1.1]heptane-7-spiro-cyclobutan]-6-yl]acetateeach as a yellow powder.

¹H-NMR(CDCl₃) δ ppm; 1.25(t, J=7 Hz, 3H), 1.80(m, 2H), 1.86(m, 2H),2.14(m, 4H), 2.25(m, 1H), 2.62(d, J=7 Hz, 2H), 2.81(d, J=11 Hz, 2H),2.87(d, J=11 Hz, 2H), 3.45(s, 2H), 4.13(q, J=7 Hz, 2H), 6.44(s, 1H),6.51(s, 1H), 6.74(d, J=(d, J=8 Hz, 1H), 6.82(d, J=8 Hz, 1H), 7.58(d, J=3Hz, 1H), 7.68(d, J=3 Hz, 1H)

¹H-NMR(CDCl₃) δ ppm; 1.25(t, J=7 Hz, 3H), 1.85(m, 3H), 1.93(br.s, 2H),2.10(br.s, 2H), 2.30(t, J=8 Hz, 2H), 2.60(d, J=8 Hz, 2H), 2.98(br.s,4H), 3.58(br.s, 2H), 4.12(q, J=7 Hz, 2H), 6.55(s, 1H), 6.75(d, J=8 Hz,1H), 6.82(d, J=8 Hz, 1H), 7.57(d, J=3 Hz, 1H), 7.68(d, J=3 Hz, 1H)

Examples 70 to 111

The compounds listed in the following tables were obtained by the samemethod as the one of Example 18.

TABLE 27 Ex. Structural formula MS M.p. NMR 70

FAB(+) 381(MH⁺) 268- 271° C. ¹H-NMR(DMSO-d₆) δppm: 1.46-1.62(m, 2H),1.74- 1.90(m, 2H), 2.02- 2.14(m, 2H), 2.68- 2.80(m, 2H), 3.28(s, 2H),3.20-3.40(m, 1H), 3.52-3.66(m, 1H), 5.53(s, 1H), 6.68(dd, J=1, 8Hz, 1H),6.80(s, # 1H), 6.82(d, J=8Hz, 1H), 7.55-7.65(m, 1H), 7.62(d, J=3Hz, 1H),9.53(s, 1H) 71

FAB(+) 383(MH⁺) 244- 245° C. ¹H-NMR(DMSO-d₆) δppm: 1.50-2.10(m, 10H),2.2- 2.3(m, 1H), 2.4-2.65(m, 2H), 3.25 and 3.28(s, 2H), 6.68(d, J=8Hz,1H), 6.78(s, 1H), 6.81(d, J=8Hz, 1H), 7.55-7.65(m, 2H), 9.53(s, 1H) 72

FAB(+) 395(MH⁺) 253- 255° C. ¹H-NMR(DMSO-d₆) δppm: 1.36-1.48(m, 1H),1.60- 1.76(m, 2H), 1.86- 1.98(m, 2H), 2.08- 2.20(m, 2H), 2.26- 2.34(m,1H), 2.68- 2.86(m, 1H), 2.90- 3.00(m, 2H), 3.14(d, J=13Hz, 1H), 3.18(d,# J=13Hz, 1H), 3.80- 3.86(m, 1H), 5.55(s, 1H), 6.70(dd, J=1, 8Hz, 1H),6.74(s, 1H), 6.85(d, J=8Hz, 1H), 7.61(d, J=3Hz, 1H), 7.63(d, J=3Hz, 1H),9.57(s, 1H), 11.9- 12.1(m, 1H)

TABLE 28 Ex. Structural formula MS M.p. NMR 73

FAB(+) 369(MH⁺) 261- 264° C. ¹H-NMR(DMSO-d₆) δppm: 1.52-1.68(m, 4H),1.98- 2.08(m, 2H), 2.25(s, 1H), 2.32-2.40(m, 2H), 2.54-2.66(m, 2H),3.26(s, 2H), 6.68(d, J=8Hz, 1H), 6.79(s, 1H), 6.81(d, J=8Hz, 1H),7.61(d, J=3Hz, # 1H), 7.63(d, J=3Hz, 1H), 9.54(s, 1H), 12.0- 12.2(m, 1H)74

FAB(+) 383(MH⁺) 272- 275° C. ¹H-NMR(DMSO-d₆) δppm: 1.38-1.40(m, 1H),1.48- 1.56(m, 2H), 1.64- 1.76(m, 2H), 2.08(br.s, 2H), 2.16(br.d, J=10Hz,2H), 2.28(br.s, 1H), 2.46-2.64(m, 1H), 2.82- 2.90(m, 2H), 3.16(s, 2H),6.69(dd, J=1, 8Hz, # 1H), 6.73(d, J=1Hz, 1H), 6.84(d, J=8Hz, 1H),7.61(d, J=3Hz, 1H), 7.63(d, J=3Hz, 1H), 9.56(s, 1H) 75

FAB(+) 383(MH⁺) 278- 281° C. ¹H-NMR(DMSO-d₆) δppm: 1.36-1.46(m, 1H),1.56- 1.68(m, 2H), 1.70- 1.80(m, 2H), 2.15(br.s, 2H), 2.22(br.d, J=11Hz,2H), 2.28(br.s, 1H), 2.50-2.70(m, 1H), 2.62(br.d, J=10Hz, 2H), 3.08(s,2H), 6.67(dd, # J=1, 8Hz, 1H), 6.70(d, J=1Hz, 1H), 6.82(d, J=8Hz, 1H),7.61(d, J=3Hz, 1H), 7.63(d, J=3Hz, 1H), 9.54(s, 1H)

TABLE 29 Ex. Structural formula MS M.p. NMR 76

FAB(+) 399(MH⁺) oily sub- stance ¹H-NMR(DMSO-d₆) δppm: 1.54(br.s, 2H),1.86- 1.96(m, 1H), 2.18- 2.28(m, 2H), 2.53(br.d, J=8Hz, 2H),2.84-2.94(m, 2H), 3.23(s, 2H), 3.57(br.d, J=8Hz, 2H), 3.72-3.84(m, 2H),# 6.74(s, 1H), 6.70- 6.80(m, 1H), 6.83(d, J=8Hz, 1H), 7.61(d, J=2Hz,1H), 7.62(d, J=2Hz, 1H), 9.52(s, 1H) 77

FAB(+) 453(MH⁺) 138- 140° C. ¹H-NMR(DMSO-d₆) δppm: 0.80(s, 9H), 1.10-1.25(m, 3H), 1.60- 2.00(m, 7H), 2.34(d, J=6.8Hz, 2H), 2.54(d, J=10.4Hz,2H), 3.17(s, 2H), 6.58(s, 1H), 6.78(d, J=8.0Hz, 1H), 6.82(d, J=8.0Hz,1H), # 7.61(d, J=2.8Hz, 1H), 7.62(d, J=2.8Hz, 1H), 9.42(s, 1H) 78

FAB(+) 411(MH⁺) 142- 146° C. ¹H-NMR(DMSO-d₆) δppm: 0.86(d, J=6.8Hz, 3H),1.32-1.43(m, 2H), 1.53-1.62(m, 2H), 1.64-1.76(m, 2H). 1.93-2.02(m, 2H),2.27(d, J=9.6Hz, 2H), 2.38(d, J=7.2Hz, 2H), 2.94(d, J=9.6Hz, 2H), #3.26(s, 2H), 6.63(s, 1H), 6.76(d, J=8.0Hz, 1H), 6.79(d, J=8.0Hz, 1H),7.55(d, J=2.8Hz, 1H), 7.56(d, J=2.8Hz, 1H)

TABLE 30 Ex. Structural formula MS M.p. NMR 79

FAB(+) 425(MH⁺) 200- 212° C. ¹H-NMR(DMSO-d₆) δppm: 0.77-0.90(m, 1H),0.92(d, J=6.8Hz, 6H), 1.35(br.s, 2H), 1.60-1.80(m, 4H), 1.91(d,J=10.4Hz, 2H), 2.32(d, J=6.8Hz, 2H), 2.53(d, J=10.4Hz, 2H), 3.20(s, 2H),6.67(d, J=8.0Hz, 1H), 6.74(s, 1H), # 6.81(d, J=8.0Hz, 1H), 7.61(d,J=2.8Hz, 1H), 7.62(d, J=2.8Hz, 1H), 9.52(s, 1H) 80

FAB(+) 411(MH⁺) 217- 218° C. ¹H-NMR(DMSO-d₆) δppm: 1.41-1.54(m, 4H),1.67- 1.77(m, 2H), 1.82-1.89(m, 2H), 1.92-2.09(m, 5H), 2.37(d, J=7.4Hz,2H), 2.56-2.62(m, 2H), 3.14(s, 2H), 6.68-6.72(m, 2H), 6.83(dd, J=1.8,7.7Hz, # 1H), 7.61(d, J=2.8Hz, 1H), 7.63(d, J=2.8Hz, 1H), 9.55(s, 1H) 81

FAB(+) 381(MH⁺) 211- 214° C. ¹H-NMR(DMSO-d₆) δppm: 0.93(s, 3H),1.23-1.29(m, 2H), 1.38(s, 3H), 1.56- 1.68(m, 4H), 1.68-1.77(m, 1H),2.03-2.10(m, 2H), 2.22(d, J=8.0Hz, 2H), 2.68-2.74(m, 2H), 3.20(s, 2H),6.64(d, J=1.5Hz, 1H), # 6.67(dd, J=1.5, 7.7Hz, 1H), 6.83(d, J=7.7Hz,1H), 7.61(d, J=2.8Hz, 1H), 7.63(d, J=2.8Hz, 1H), 9.50(s, 1H)

TABLE 31 Ex. Structural formula MS M.p. NMR 82

FAB(+) 411(MH⁺) 126- 128° C. ¹H-NMR(CD₃OD) δppm: 1.11(d, J=7Hz, 3H),1.49- 1.56(m, 1H), 1.58-1.62(d, J=11Hz, 1H), 1.63-1.74(m, 3H),1.81-1.83(dd, J=4, 9Hz, 1H), 1.86-1.94(m, 2H), 2.38-2.42(br.d, J=11Hz,1H), 2.57- # 2.62(br.d, J=11Hz, 1H), 2.64-2.80(m, 4H), 3.27(s, 2H),6.67(s, 1H), 6.79(s, 2H), 7.55(d, J=3Hz, 1H), 7.57(d, J=3Hz, 1H) 83

FAB(+) 411(MH⁺) 233- 234° C. ¹H-NMR(CD₃OD) δppm: 1.11(d, J=7Hz, 3H),1.46- 1.58(m, 4H), 1.65(br.s, 1H), 1.64-1.74(m, 1H), 1.83(br.s, 1H),1.89- 2.00(m, 1H), 2.27(t, J=10Hz, 2H), 2.56-2.66(m, 1H), 2.76-2.83(dt,J=7, # 11Hz, 1H), 2.96(d, J=11Hz, 1H), 3.04(d,J=11Hz, 1H), 3.26(s, 2H),6.67(s, 1H), 6.79(s, 2H), 7.55(d, J=3Hz, 1H), 7.57(d, J=3Hz, 1H) 84

FAB(+) 439(MH⁺) 104- 108° C. ¹H-NMR(DMSO-d₆) δppm: 1.24(d, J=7.0Hz, 3H),1.34-1.83(m, 12H), 2.13- 2.23(m, 2H), 2.46(m, 1H), 2.59(m, 1H), 2.88-2.98(br.s, 2H), 3.22(br.s, 2H), 6.65(br.s, 1H), 6.69- 6.83(m, 2H),7.35(d, # J=2.7Hz, 1H), 7.60(d, J=2.7Hz, 1H), 8.97(br.s, 1H)

TABLE 32 Ex. Structural formula MS M.p. NMR 85

FAB(+) 409(MH⁺) 175- 180° C. ¹H-NMR(CD₃OD) δppm: 1.88(m, 2H), 1.99(m,2H), 2.26(s, 2H), 2.38(t, J=8Hz, 2H), 2.54-2.60(m, 1H), 2.68(d, J=8Hz,2H), 3.46(d, J=12Hz, 2H), 3.63(d, J=12Hz, 2H), 4.08(s, 2H), 6.84(s, #1H), 6.95(d, J=8Hz, 1H), 6.99(d, J=8Hz, 1H), 7.61(s, 2H) 86

FAB(+) 409(MH⁺) 90- 92° C. ¹H-NMR(CD₃OD) δppm: 1.78-1.85(m, 2H), 1.90-1.94(m, 2H), 2.14- 2.18(m, 4H), 2.46- 2.52(m, 1H), 2.59(d, J=7Hz, 2H),2.89(d, J=11Hz, 2H), 2.97(d, J=11Hz, 2H), 3.49(s, 2H), 6.67(d, J=2Hz,1H), # 6.76(dd, J=2, 8Hz, 1H), 6.79(d, J=8Hz, 1H), 7.55(d, J=3Hz, 1H),7.57(d, J=3Hz, 1H) 87

FAB(+) 473(MH⁺) 128- 131° C. ¹H-NMR(DMSO-d₆) δppm: 1.59-1.96(m, 10H),2.21(d, J=10Hz, 2H), 2.93(d, J=10Hz, 2H), 3.23(s, 2H), 6.73(s, 1H),6.77(d, J=8.0Hz, 1H), 6.89(d, J=8.0Hz, 1H), 7.10-7.20(m, 2H),7.25-7.35(m, 3H), # 7.61(d, J=2.8Hz, 1H), 7.63(d, J=2.8Hz, 1H), 9.56(s,1H)

TABLE 33 Ex. Structural formula MS M.p. NMR 88

FAB(+) 409(MH⁺) 254- 259° C. ¹H-NMR(DMSO-d₆) δppm: 1.16(m, 1H),1.41-1.70(m, 7H), 1.84-1.98(m, 4H), 2.37(m, 1H), 2.43-2.56(m, 2H),3.26(s, 2H), 6.72(dd, J=1.5, 7.9Hz, 1H), 6.83(d, J=7.9Hz, 1H), 6.84(d,J=1.5Hz, 1H), 7.63(d, # J=2.9Hz, 1H), 7.64(d, J=2.9Hz, 1H), 9.55(s, 1H),12.02(br.s, 1H) 89

FAB(+) 411(MH⁺) ¹H-NMR(DMSO-d₆) δppm: 0.99(d, J=7.2Hz, 3H), 1.03(d,J=7.2Hz, 3H), 1.57- 1.74(m, 5H), 1.80(t, J=8.0Hz, 1H), 1.95(d, J=8.0Hz,1H), 2.02(d, J=8.0Hz, 1H), 2.24(d, J=7.6Hz, 1H), 2.57(d, J=10Hz, 1H),2.75(d, # J=10Hz, 1H), 3.18(d, J=12.8Hz, 1H), 3.29(d, J=12.8Hz, 1H),6.67(d, J=8.0Hz, 1H), 6.72(s, 1H), 6.81(d, J=8.0Hz, 1H), 7.60(d,J=2.8Hz, 1H), 7.62(d, J=2.8Hz, 1H), 9.53(s, 1H), 12.0(br.s, 1H) 90

FAB(+) 383(MH⁺) 186- 188° C. ¹H-NMR(DMSO-d₆) δppm: 1.46-1.72(m, 6H),1.82(m, 1H), 1.91(m, 1H), 2.02- 2.13(m, 2H), 2.71(m, 1H), 2.79(m, 1H),2.93(m, 1H), 3.12(d, J=13.4Hz, 1H), 3.25(d, J=13.4Hz, 1H), 6.70(dd,J=1.2, 7.9Hz, 1H), # 6.74(d, J=1.2Hz, 1H), 6.86(d, J=7.9Hz, 1H), 7.63(d,J=2.9Hz, 1H), 7.64(d, J=2.9Hz, 1H), 9.58(s, 1H), 12.20(br.s, 1H)

TABLE 34 Ex. Structural formula MS M.p. NMR 91

FAB(+) 411(MH⁺) 125- 130° C. ¹H-NMR(DMSO-d₆) δppm: 1.00(d, J=7Hz, 3H),1.10- 1.20(m, 1H), 1.30-1.45(m, 1H), 1.50(br.s, 1H), 1.60(br.s, 1H),1.70- 1.90(m, 3H), 2.08(d, J=8Hz, 1H), 2.14(d, J=8Hz, 1H), 2.3-2.5(m,2H), 2.68(m, 1H), 2.73(d, # J=10Hz, 1H), 2.82(d, J=10Hz, 1H), 3.13(d,J=13Hz, 1H), 3.20(d, J=13Hz, 1H), 6.67(d, J=8Hz, 1H), 6.72(s, 1H),6.82(d, J=8Hz, 1H), 7.06(d, J=3Hz, 1H), 7.62(d, J=3Hz, 1H), 9.54(s, 1H),12.3(br.s, 1H) 92

FAB(+) 411(MH⁺) 223- 225° C. ¹H-NMR(DMSO-d₆) δppm: 1.33-1.48(m, 4H),1.54- 1.78(m, 6H), 2.08-2.21(m, 4H), 2.54(m, 1H), 2.84- 2.91(m, 2H),3.17(s, 2H), 6.70(dd, J-1.5, 7.9Hz, 1H), 6.73(d, J=1.5Hz, 1H), 6.84(d,J=7.9Hz, # 1H), 7.63(d, J=2.7Hz, 1H), 7.64(d, J=2.7Hz, 1H), 9.56(s, 1H)93

FAB(+) 439(MH⁺) ¹H-NMR(DMSO-d₆) δppm: 0.84-1.00(m, 1H), 0.95(d, J=6.8Hz,3H), 0.98(d, J=6.8Hz, 3H), 1.06(d, J=6.8Hz, 3H), 1.28- 1.38(m, 2H),1.54-1.82(m, 4H), 1.87(d, J=7.2Hz, 1H), 1.89(d, J=7.2Hz, 1H),2.48-2.55(m, 1H), # 2.55(d, J=7.2Hz, 1H), 2.60(d, J=7.2Hz, 1H), 3.24(s,2H), 6.68(d, J=8.0Hz, 1H), 6.75(s, 1H), 6.84(d, J=8.0Hz, 1H), 7.61(d,J=2.8Hz, 1H), 7.63(d, J=2.8Hz, 1H), 9.52(br.s, 1H), 12.0(br.s, 1H)

TABLE 35 Ex. Structural formula MS M.p. NMR 94

FAB(+) 503 (MH⁺) 234- 236° C. ¹H-NMR(DMSO-d₆) δppm: 1.30-1.50(m, 3H),1.55- 1.60(br.s, 3H), 1.70- 1.85(m, 2H),1.80-1.95(m, 2H), 2.15(br.d,J=10Hz, 2H), 2.50-2.60(m, 1H), 2.87(br.d, J=11Hz, 2H), # 3.15(s, 2H),3.95-4.05(m, 2H), 6.68(d, J=8Hz, 1H), 6.72(s, 1H), 6.83(d, J=8Hz, 1H),7.16(dd, J=2.8Hz, 1H), 7.37(t, J=8Hz, 1H), 7.40(s, 1H), 7.49(d, J=8Hz,1H), 7.60(d, J=3Hz, 1H), 7.62(d, J=3Hz, 1H), 9.56(s, 1H), 12.97(br.s,1H) 95

FAB(+) 441 (MH⁺) 108- 113° C. ¹H-NMR(DMSO-d₆) δppm: 1.30-1.45(m, 3H),1.45- 1.60(m, 3H), 1.60-1.80(m, 4H), 2.06-2.20(m, 2H), 2.50(m, 1H),2.80-2.90(m, 2H), 3.15(s, 2H), 3.43(t, J=6Hz, 2H), 3.93(s, 2H), #6.68(d, J=8Hz, 1H), 6.72(s, 1H), 6.83(d, J=8Hz, 1H), 7.61(d, J=3Hz, 1H),7.62(d, J=3Hz, 1H), 9.55(s, 1H) 96

FAB(+) 517 (MH⁺) 208- 210° C. ¹H-NMR(DMSO-d₆) δppm: 1.36-1.50(m, 3H),1.63(br.s, 3H), 1.7- 1.86(m, 2H), 1.80-1.92(m, 2H), 2.15(br.d, J=11Hz,2H), 2.46-2.64(m, 1H), 2.87(br.d, J=10Hz, 2H), 3.16(s, 2H), 3.45(s, 2H),# 3.95(t, J=7Hz, 2H), 6.69(d, J=7Hz, 1H), 6.73(s, 1H), 6.83(d, J=7Hz,1H), 6.84(d, J=8Hz, 2H), 7.12(d, J=8Hz, 2H), 7.61(d, J=3Hz, 1H), 7.62(d,J=3Hz, 1H). 9.55(s, 1H), 12.21(s, 1H)

TABLE 36 Ex. Structural formula MS M.p. NMR 97

δ ppm: 0.97(d, J=7.1Hz, 3H), 1.06(d, J=7.1Hz, 3H), 1.44(m, 1H), 1.52(m,1H), 1.63(m, 1H), 1.69(m, 1H), 2.09(m, 1H), 2.23(d, J=10.6Hz, 1H), 2.26-2.34(m, 2H), 2.38(dd, J=7.5, 15.6Hz, 1H), 2.42-2.52(m, 2H), 3.23(d,J=13.0Hz, 1H), 3.32(d, J=13.0Hz, 1H), 6.69(dd, J=1.5, 7.7Hz, 1H), #6.73(d, J=1.5Hz, 1H), 6.83(d, J=7.7Hz, 1H), 7.62(d, J=2.9Hz, 1H),7.63(d, J=2.9Hz, 1H), 9.54(s, 1H), 12.02(s, 1H) 98

FAB(+) 383(MH⁺) ¹H-NMR(DMSO-d₆) δ ppm: 1.28(m, 1H), 1.46(m, 1H),1.68-1.78(m, 4H), 2.11- 2.18(m, 2H), 2.24-2.33(m, 2H), 2.41(m, 1H),2.59- 2.66(m, 2H), 3.18(s, 2H), 6.58(d, J=1.6Hz, 1H), 6.65(d, J=7.9Hz,1H), 6.83(dd, J=1.6, 7.9Hz, 1H), 7.63(d, J=2.9Hz, 1H), 7.64(d, J=2.9Hz,1H), 9.37(s, 1H), 11.54(br.s, 1H) 99

FAB(+) 425(MH⁺) 226- 229° C. ¹H-NMR(DMSO-d₆) δ ppm: 0.66(s, 6H),1.21-1.39(m, 6H), 1.57(t, J=5.9Hz, 1H), 1.78(d, J-11.8Hz, 2H), 2.20(d,J=5.9Hz, 2H), 2.40(d, J=11.8Hz, 2H), 3.08(s, 2H), 6.67(dd, J=1.0, 7.7Hz,1H), 6.70(d, J=1.0Hz, 1H), 6.83(d, J=7.7Hz, 1H), 7.61(d, J=2.6Hz, 1H),7.62(d, J=2.6Hz, 1H), 9.54(s, 1H), 12.00(s, 1H)

TABLE 37 Ex. Structural formula MS M.p. NMR 100

110- 115° C. ¹H-NMR(CDCl₃) δ ppm: 0.97(d, J=7.6Hz, 3H), 0.99(d, J=7.6Hz,3H), 1.21(d, J=6.8Hz, 3H), 1.30-2.00(m, 12H), 2.38- 2.64(m, 4H), 3.25(s,2H), 6.56(s, 1H), 6.66-6.82(m, 2H), 7.42(d, J=2.8Hz, 1H), 7.63(d,J=2.8Hz, 1H), 8.03(s, 1H) 101

FAB(+) 439(MH⁺) 110- 115° C. ¹H-NMR(DMSO-d₆) δ ppm: 0.76-0.87(m, 1H),0.93(d, J=6.4Hz, 6H), 1.50- 1.90(m, 1H), 1.32-1.39(m, 2H), 1.56-1.78(m,5H), 1.84(d, J=9.6Hz, 2H), 2.17(t, J=7.2Hz, 2H), 2.52(d, J=10Hz, 2H),3.19(s, 2H), 6.67(d, J=8Hz, 1H), 6.74(s, 1H), 6.81(d, J=8Hz, 1H),7.61(d, J=2.8Hz, 1H), 7.62(d, J=2.8Hz, 1H), 9.52(s, 1H) 102

98- 105° C. ¹H-NMR(DMSO-d₆) δ ppm: 0.92(d, J=6.8Hz, 6H), 1.38-1.92(m,13H), 2.01(t, J=6.4Hz, 2H), 2.52(d, J=10.8Hz, 2H), 3.18(s, 2H), 6.67(d,J=8.4Hz, 1H), 6.74(s, 1H), 6.82(d, J=8.4Hz, 1H), 7.60(d, J=2.4Hz, 1H),7.62(d, J=2.4Hz, 1H), 9.53(s, 1H)

TABLE 38 Ex. Structural formula MS M.p. NMR 103

FAB(+) 427(MH⁺) 217- 219° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.30-1.46(m, 3H),1.84- 2.00(m, 4H), 2.40-2.60(m, 3H), 2.66(s, 2H), 2.68- 2.78(m, 2H),3.15(s, 3H), 3.22(s, 2H), 6.68(dd, J=1, 8Hz, 1H), 6.71(s, 1H), 6.83(d,J=8Hz, 1H), 7.61(d, J=3Hz, 1H), 7.63(d, J=3Hz, 1H), 9.56(s, 1H) 104

FAB(+) 397(MH⁺) 215- 217° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.32-1.54(m, 5H),1.62- 1.74(m, 2H), 1.83-1.90(m, 2H), 1.96(s, 2H), 2.06(m, 1H),2.64-2.85(m, 3H), 3.12(d, J=13.7Hz, 1H), 3.16(d, J=13.7Hz, 1H), 6.69(dd,J=1.5, 7.9Hz, 1H), 6.73(d, J=1.5Hz, 1H), 6.85(d, J=7.9Hz, 1H), 7.63(d,J=2.9Hz, 1H), 7.64(d, J=2.9Hz, 1H), 9.57(s, 1H) 105

FAB(+) 427(MH⁺) 225- 228° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.30-1.45(m, 1H),1.56- 1.68(m, 2H), 1.70-1.90(m, 3H), 1.99(br.s, 1H), 2.16(s, 2H),2.34-2.70(m, 5H), 3.13(s, 2H), 3.15(s, 3H), 6.70(d, J=8Hz, 1H), 6.72(s,1H), 6.83(d, J=8Hz, 1H), 7.61(d, J=3Hz, 1H), 7.63(d, J=3Hz, 1H), 9.56(s,1H)

TABLE 39 Ex. Structural formula MS M.p. NMR 106

FAB(+) 409(MH⁺⁾ 263- 266° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.44-1.60(m, 6H),1.64- 1.79(m, 4H), 1.84(m, 1H), 1.93(m, 1H), 2.45- 2.57(m, 3H), 3.26(s,2H), 6.46(dd, J=1.6, 7.9Hz, 1H), 6.83(d, J=1.6Hz, 1H), 6.84(d, J=7.9Hz,1H), 7.63(d, J=2.7Hz, 1H), 7.64(d, J=2.7Hz, 1H), 9.56(s, 1H),12.06(br.s, 1H) 107

ESI397.1 (MH⁺) 206- 209° C. ¹H-NMR(DMSO-d₆) δ ppm: 0.96(m, 1H), 1.07-1.18(m, 2H), 1.70(m, 1H), 1.79-1.94(m, 7H), 2.15(d, J=6.0Hz, 2H),2.42-2.50(m, 2H), 3.23(s, 2H), 6.73(dd, J=1.5, 7.9Hz, 1H), 6.77(d,J=1.5Hz, 1H), 6.84(d, J=7.9Hz, 1H), 7.63(d, J=2.9Hz, 1H), 7.64(d,J=2.9Hz, 1H), 9.58(s, 1H), 11.97(br.s, 1H) 108

FAB(+) 437(MH⁺) 199- 201° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.22-1.82(m, 9H),2.02- 2.38(m, 3H), 2.26(d, J=8Hz, 2H), 2.22-2.38(m, 2H), 2.44-2.66(m,3H), 3.08(s, 2H), 6.67(d, J=8Hz, 1H), 6.70(d, J=8Hz, 1H), 6.82(d, J=8Hz,1H), 7.61(d, J=3Hz, 1H), 7.62(d, J=3Hz, 1H), 9.54(s, 1H), 11.93(s, 1H)

TABLE 40 Ex. Structural formula MS M.p. NMR 109

FAB(+) 465(MH⁺) 205- 206° C. ¹H-NMR(DMSO-d₆) δ ppm: 0.68(q, J=12Hz, 1H),0.95(d, J=7Hz, 3H), 0.99(d, J=7Hz, 3H), 1.21(m, 1H), 1.34-1.50(m, 3H),1.58(m, 1H), 1.80(m, 2H), 1.90(d, J=9Hz, 1H), 2.00-2.16(m, 3H), 2.16-2.30(m, 2H), 2.26(d, J=8Hz, 2H), 2.39(m, J=8Hz, 1H), 3.13(s, # 2H),6.66(d, J=8Hz, 1H), 6.72(s, 1H), 6.80(d, J=8Hz, 1H), 7.60(d, J=3Hz, 1H),7.62(d, J=3Hz, 1H), 9.51(s, 1H), 11.9(s, 1H) 110

FAB(+) 409(MH³⁰) 263- 266° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.26-1.36(m, 2H),1.46- 1.55(m, 2H), 1.56-1.65(m, 2H), 1.93-2.01(m, 2H), 2.58(s, 1H),2.62-2.74(m, 3H), 3.13(s, 2H), 6.77(d, J=7.9Hz, 1H), 6.84(d, J=7.9Hz,1H), 6.87(s, 1H), 7.29(dd, J=1.1, 6.8Hz, 1H), 7.63(d, J=2.9Hz, 1H), #7.64(d, J=2.9Hz, 1H), 9.56(s, 1H), 12.11(s, 1H) 111

FAB(+) 423(MH⁺) 98- 101° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.22-1.32(m, 1H),1.42- 1.80(m, 6H), 1.86(dd, J=8, 12Hz, 1H), 1.93(dd, J=8, 12Hz, 1H),2.04- 2.18(m, 3H), 2.23(br.d, J=11Hz, 1H), 2.42-2.66(m, 1H), 2.59(br.t,J=12Hz, 2H), 2.83(m, 1H), 3.09(s, 2H), 6.66(dd, J=2, # 8Hz, 1H), 6.70(s,1H), 6.82(d, J=8Hz, 1H), 7.61(d, J=2Hz, 1H), 7.62(d, J=2Hz, 1H), 9.55(s,1H), 12.0(s, 1H)

Examples 112 to 116

The following compounds were obtained by the same methods as those ofExamples 13 and 14 (optionally using anhydrous potassium carbonate as asubstitute for diisopropylamine) and that of Example 18.

TABLE 41 Ex. Structural formula MS M.p. NMR 112

FAB(+) 449(MH⁺), 451(MH⁺) 249- 251° C. ¹H-NMR(DMSO-d₆) δ ppm: 0.58(s,6H), 1.28- 1.38(m, 2H), 1.38- 1.55(m, 3H), 1.76(d, J=1.7Hz, 3H),1.82(br.d, J=11.5Hz, 2H), 2.00(br.d, J=11.9Hz, 1H), 2.67(br.d, J=11.5Hz,2H), 2.74- 2.89(m, 1H), 3.13(s, 2H), 6.68(d, J=8.1Hz, # 1H), 6.73(d,J=1.1Hz, 1H), 6.84(dd, J=1.1, 8.1Hz, 1H), 6.85(dd, J=1.7, 11.9Hz, 1H),7.60-7.64(m, 2H), 9.56(s, 1H), 12.18- 12.25(br.s, 1H) 113

FAB(+) 397(MH⁺) 264- 265° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.18(s, 3H), 1.27-1.35.(m, 1H), 1.53- 1.61(m, 2H), 1.75- 1.88(m, 5H), 2.53- 2.64(m, 4H),3.23(s, 2H), 6.68(dd, J=1.8Hz, 1H), 6.72(d, J=1Hz, 1H), 6.83(d, J=8Hz,1H), 7.61(d, J=3Hz, 1H), 7.62(d, J=3Hz, 1H), 9.44(br.s, 1H) 114

FAB(+) 413(MH⁺) 223- 225° C. (dec) ¹H-NMR(DMSO-d₆) δ ppm: 1.39-1.49(m,1H), 1.60- 1.72(m, 2H), 1.88- 1.96(m, 2H), 2.10- 2.19(m, 2H), 2.69-2.84(m, 1H), 2.88- 2.99(m, 3H), 3.14(d, J=12.3Hz, 1H), 3.20(d, J-12.3Hz,1H), 3.61- 3.67(m, 1H), 6.70(d, J=7.6Hz, 1H), 6.74(d, J=1.0Hz, # 1H),6.85(dd, J=1.0, 7.6Hz, 1H), 7.61(d, J=2.8Hz, 1H), 7.63(d, J=2.8Hz, 1H),9.57(s, 1H)

TABLE 42 Ex. Structural formula MS M.p. NMR 115

FAB(+) 415(MH⁺) 185- 187° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.40-1.55(m, 3H),1.58- 1.90(m, 4H), 2.08-2.18(m, 2H), 2.50-2.68(m, 1H), 2.83-2.95(m, 2H),3.13- 3.18(m, 1H), 3.17(s, 2H), 5.18(dd, J=10.6, 49.6Hz, 1H), 6.68(d,J=8.2Hz, 1H), 6.73(s, 1H), 6.84(d, J=8.2Hz, 1H), 7.60- 7.64(m, 2H),9.57(s, 1H) 116

FAB(+) 397(MH⁺) 183- 185° C. ¹H-NMR(CD₃OD) δ ppm: 1.28(s, 3H),1.41-1.52(m, 1H), 1.56(dd, J=6, 12Hz, 2H), 1.98(m, 3H), 2.08(s, 2H),2.57(m, 2H), 2.73(m, 2H), 3.24(s, 2H), 6.64(d, J=2Hz, 1H), 6.77(dd, J=2,8Hz, 1H), 6.79(d, J=8Hz, 1H), 7.55(d, J=3Hz, 1H), 7.57(d, J=3Hz, 1H)

Examples 117 to 119

The following compounds were obtained from known compounds by the samemethods as those of Examples 12, 13 and 14 (using anhydrous potassiumcarbonate as a substitute for diisopropylamine) and that of Example 18.

TABLE 43 Ex. Structural formula MS M.p. NMR 117

FAB(+) 383(MH⁺) 155- 158° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.15-1.23(m, 2H),1.51- 1.60(m, 2H), 1.88- 1.96(m, 2H), 1.97- 2.05(m, 2H), 2.07- 2.19(m,1H), 2.30(d, J=8.4Hz, 2H), 2.97- 3.06(m, 2H), 3.26(s, 2H), 6.72(dd,J=1.6, 8.2Hz, 1H), 6.80(d, J=8.2Hz, 1H), 6.84(d, J=1.6Hz, 1H), 7.61(d,J=2.6Hz, 1H), 7.62(d, J=2.6Hz, 1H), 9.45(s, 1H) 118

FAB(+) 381(MH⁺) 206- 208° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.27(m, 2H), 1.77-1.88(m, 2H), 1.88- 1.98(m, 1H), 2.12- 2.23(m, 1H), 2.49- 2.57(m, 1H),3.12- 3.22(m, 2H), 3.34- 3.51(m, 3H), 5.60(s, 1H), 6.75(d, J=8.6Hz, 1H),6.82(d, J=8.6Hz, 1H), 6.87(s, 1H), 7.60(d, J=2.7Hz, 1H), 7.61(d,J=2.7Hz, 1H), 9.46(s, 1H) 119

FAB(+) 369(MH⁺) 158° C. (dec) ¹H-NMR(DMSO-d₆) δ ppm: 1.49-1.58(m, 4H),1.65- 1.74(m, 2H), 1.86- 1.94(m, 2H), 2.44- 2.55(m, 1H), 3.05- 3.11(m,2H), 3.29(s, 2H), 6.71(dd, J=1.3, 8.0Hz, 1H), 6.81(d, J=8.0Hz, 1H),6.87(d, J=1.3Hz, 1H), 7.61(d, J=2.9Hz, 1H), 7.62(d, J=2.9Hz, 1H),9.48(s, 1H)

Example 120

The following compound was obtained by treating(6R*,8R*)-3-(3,6,8-trimethyl-3-azabicyclo[3.3.1]non-9-yl)-2-methylpropanoicacid by the same methods as those of Examples 12, 13 and 14 (usinganhydrous potassium carbonate as a substitute for diisopropylamine) andthat of Example 18.

TABLE 44 Ex. Structural formula MS M.p. NMR 120

FAB(+) 453(MH⁺) 110- 115° C. ¹H-NMR(DMSO-d₆) δ ppm: 0.75-0.90(m, 1H),0.94(d, J=6.8Hz, 6H), 1.00(d, J=6.8Hz, 3H), 1.14- 1.43(m, 4H),1.55-1.78(m, 5H), 1.85(d, J=10.8Hz, 2H), 2.52(d, J=10.8Hz, 2H), 2H),3.19(s, 2H), 6.67(d, J=7.6Hz, 1H), 6.73(s, 1H), 6.81(d, J=7.6Hz, 1H),7.61(d, J=2.8Hz, 1H), 7.62(d, J=2.8Hz, 1H), 9.51(s, 1H)

Example 121

The following compound was obtained by treating ethyl4-[2-[(anti)-3-methyl-3-azabicyclo[3.3.1]non-9-yl]ethyloxy]benzoate bythe same methods as those of Examples 17 and 18.

TABLE 45 Ex. Structural formula MS M.p. NMR 121

FAB(+) 503 (MH⁺) 239- 242° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.35-1.50(m, 3H),1.62(br.s, 3H), 1.65- 1.75(m, 2H), 1.80-1.95(m, 2H), 2.14(br.d, J=10Hz,2H), 2.45-2.65(m, 1H), 2.87(br.d, J=10Hz, 2H), 3.15(s, 2H), # 4.05(t,J=6Hz, 2H), 6.68(d, J=8Hz, 1H), 6.72(s, 1H), 6.83(d, J=8Hz, 1H), 6.98(d,J=8Hz, 1H), 7.61(s, 2H), 7.85(d, J=8Hz, 2H), 9.55(s, 1H), 12.58(br.s,1H)

Example 122

The following compound was obtained by treatingethyl(11-hydroxy-9-methyl-9-azabicyclo[5.3.1]undec-11-yl)acetate by thesame methods as those of Examples 12, 13, 14 and 18.

TABLE 46 Ex. Structural formula MS M.p. NMR 122

FAB(+) 441(MH⁺) 217- 218° C. (dec) ¹H-NMR(CDCl₃) δ ppm: 1.10-1.25(m,2H), 1.50- 1.65(m, 4H), 1.77- 1.93(m, 4H), 1.97- 2.09(m, 2H), 2.23-2.32(m, 2H), 2.70- 2.77(m, 2H), 2.79(s, 2H), 3.23(s, 2H), 6.45(d,J=1.6Hz, 1H), 6.74(s, 1H), 6.79(d, J=7.8Hz, 1H), 6.85(dd, J=1.6, 7.8Hz,1H), 7.27(d, J=3.1Hz, 1H), 7.59(d, J=3.1Hz, # 1H), 8.85-9.04(br.s. 1H)

Example 123

The following compound was obtained by treatingethyl(3-benzyl-7-methyl-3,7-diazabicyclo[3.3.1]non-9-ylidene)acetate bythe same methods as those of Examples 64 and 18.

TABLE 47 Ex. Structural formula MS M.p. NMR 123

FAB(+) 412(MH⁺) 220° C. (dec) ¹H-NMR(CDCl₃) δ ppm: 2.00-2.04(m, 2H),2.13- 2.20 and 2.24-2.30(m, 1H)(3:7)), 2.35 and 2.37(d, J=8.5Hz,2H(7:3)), 2.80 and 2.82(s, 3H(7:3)), 2.50- 2.56 and 2.73-2.79(m,2H(3:7)), 2.89-2.95 and 3.18-3.23(m, 2H(7:3)), # 3.16-3.21 and 3.28-3.48(m, 2H(7:3)), 3.35- 3.41 and 3.55-3.60(m, 2H(3:7)), 3.47 and 3.49(s,2H(3:7)), 6.59- 6.62(m, 1H), 6.78- 6.82(m, 1H), 6.87(d, J=7.9Hz, 1H),7.58(d, J=3.0Hz, 1H), 7.59(d, J=3.0Hz, 1H)

Production Example 84(anti)-3-(Vinyloxycarbonyl)-9-aminomethyl-3-azabicyclo[3.3.1]nonane

To 10 ml of benzene were added 500 mg of(anti)-[3-(vinyloxycarbonyl)-3-azabicyclo[3.3.1]non-9-yl]acetic acid,0.31 ml of triethylamine and 0.45 ml of diphenylphosphoryl azide and theresulting mixture was stirred at 80° C. for 3 hours. After concentratingthe reaction mixture, a colorless oily substance was obtained. This oilysubstance was dissolved in 10 ml of tetrahydrofuran and 5.0 ml of 1 Nsodium hydroxide was added thereto. After stirring at room temperaturefor 30 minutes, water was added to the reaction mixture followed by theextraction with chloroform. Then it was dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (eluted with methylenechloride/methanol/conc. aqueous ammonia) to thereby give 342 mg of thetitle compound as a colorless oily substance.

¹H-NMR(CDCl₃) δ ppm; 1.46(m, 1H), 1.57-1.95(m, 10H), 2.91(d, J=7.5 Hz,2H), 3.11(m, 1H), 3.18(m, H), 4.18-4.28(m, 2H), 4.45(dd, J=1.5, 6.2 Hz,1H), 4.79(dd, J=1.5, 13.9 Hz, 1H), 7.25(dd, J=6.2, 13.9 Hz, 1H)

Production Example 85N-[(anti)-3-(Vinyloxycarbonyl)-3-azabicyclo[3.3.1]non-9-yl]methyl-N′,N′-dimethylsulfamide

342 mg of(anti)-3-(vinyloxycarbonyl)-9-aminomethyl-3-azabicyclo[3.3.1]nonane wasdissolved in 10 ml of methylene chloride. After adding 0.25 ml oftriethylamine, the resulting mixture was ice-cooled. Then 0.2 ml ofdimethylsulfamoyl chloride was dropped thereinto and the mixture wasstirred at room temperature for 14 hours. After further adding 0.25 mlof triethylamine and 0.2 ml of dimethylsulfamoyl chloride, the reactionmixture was stirred at room temperature for additional 4 hours. Then thereaction mixture was concentrated and the residue was purified by silicagel column chromatography (eluted with n-hexane/ethyl acetate) tothereby give 406 mg of the title compound as a colorless oily substance.

¹H-NMR(CDCl₃) δ ppm; 1.46-1.89(m, 9H), 2.83(s, 6H), 3.10(m, 1H), 3.18(m,1H), 3.23-3.30(m, 2H), 4.05(br.s, 1H), 4.20-4.29(m, 2H), 4.46(dd, J=1.6,6.2 Hz, 1H), 4.79(dd, J=1.6, 14.1 Hz, 1H), 7.24(dd, J=6.2, 14.1 Hz, 1H)

Production Example 86(anti)-1-(3-Methyl-3-azabicyclo[3.3.1]non-9-yl)-2-methyl-2-propanol

To 5 ml of ether was added 13 ml of a solution of methylmagnesium iodidein ether (ca 2M). Next, 10 ml of a solution of 2.25 g of ethyl(anti)-(3-methyl-3-azabicyclo-[3.3.1]non-9-yl)acetate in ether wasdropped at room temperature thereinto and the resulting mixture washeated under reflux for 2 hours. After adding a saturated aqueoussolution of ammonium chloride, the reaction mixture was extracted withether. The ether layer was washed with water and saturated aqueoussolution of sodium chloride, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The obtained residue was purifiedby alumina chromatography (eluted with n-hexane/ethyl acetate) tothereby give 1.01 g of the title compound as a colorless oily substance.

¹H-NMR(CDCl₃) δ ppm; 1.18(s, 1H), 1.24(s, 6H), 1.39(m, 1H), 1.48-1.66(m,7H), 1.72-1.84(m, 2H), 2.13(s, 3H), 2.18-2.27(m, 2H) 2.42(m, 1H),2.85-2.94(m, 2H)

Production Example 87(anti)-1-(3-Azabicyclo[3.3.1]non-9-yl)-2-methyl-2-propanol hydrochloride

To 0.91 g of(anti)-1-[3-methyl-3-azabicyclo[3.3.1]-non-9-yl]-2-methyl-2-propanol wasadded 0.7 ml of 1-chloroethyl chloroformate and the resulting mixturewas stirred at room temperature for 30 minutes and then heated to 60° C.for 1 hour. After concentrating the reaction mixture under reducedpressure, 10 ml of ethanol was added to the residue and the mixture washeated at 60° C. for 1 hour. The reaction mixture was concentrated underreduced pressure and the crystals thus obtained were washed with ethylacetate to thereby give 740 mg of the title compound as a slightlyyellow powder.

¹H-NMR(DMSO-d₆) δ ppm; 1.17(s, 6H), 1.45-1.60(m, 6H), 1.70-1.92(m, 6H),3.08-3.19(m, 2H), 3.21-3.28(m, 2H), 4.18(br.s, 1H)

Production Example 88 Ethyl(anti)-2-[3-(vinyloxycarbonyl)-3-azabicyclo[3.3.1]non-9-yl)-2-methylpropionate

To 40 ml of dry tetrahydrofuran was added 9.04 ml of diisopropylamineand the resulting mixture was cooled to −60° C. Then 40.3 ml of a 1.6 Msolution of n-butyllithium in hexane was added thereto and the resultingmixture was stirred for 50 minutes. After dropping 10 ml of a solutionof 3.08 g of ethyl(anti)-2-(3-methyl-azabicyclo[3.3.1]non-9-yl)propionate intetrahydrofuran, the resulting mixture was stirred at 0° C. for 30minutes. After cooling the mixture to −60° C. again, 4.02 ml of methyliodide was dropped thereinto and the reaction mixture was stirred atroom temperature for 3 days. After adding ice/water, the reactionmixture was extracted with ethyl acetate. Then the ethyl acetate layerwas washed with water and a saturated aqueous solution of sodiumchloride, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluted with n-hexane/ethyl acetate) to thereby give 2.82g of a pale yellow oily substance.

This oily substance was dissolved in 10 ml of 1,2-dichloroethane and 1.5ml of vinyl chloroformate was added thereto. The obtained mixture wasstirred at room temperature for 35 minutes and then heated under refluxfor 9.5 hours. The reaction mixture was concentrated under reducedpressure and ice/water was added thereto followed by the extraction withethyl acetate. The ethyl acetate layer was washed with 1 N hydrochloricacid, water, a saturated aqueous solution of sodium hydrogencarbonateand a saturated aqueous solution of sodium chloride, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (eluted withn-hexane/ethyl acetate) to thereby give 1.03 g of the title compound asa slightly yellow oily substance.

¹H-NMR(CDCl₃) δ ppm; 1.26(t, J=7.1 Hz, 3H), 1.31(s, 6H), 1.45(m, 1H),1.56-2.06(m, 8H), 3.12(m, 1H), 3.20(m, 1H), 4.10-4.20(m, 4H), 4.44(dd,J=1.6, 6.2 Hz, 1H), 4.78(dd, J=1.6, 14.1 Hz, 1H), 7.24(dd, J=6.2, 14.1Hz, 1H)

Production Example 89 Ethyl(anti)-2-(3-Azabicyclo[3.3.1]non-9-yl)-2-methylpropionate

To 1.03 g of ethyl(anti)-2-[3-(vinyloxycarbonyl)-3-azabicyclo[3.3.1]non-9-yl]-2-methylpropionatewas added 5 ml of 4 N hydrogenchloride in dioxane and the resultingmixture was stirred at room temperature for 30 minutes. The reactionmixture was concentrated under reduced pressure and 20 ml of ethanol wasadded to the residue. Then the resulting mixture was heated under refluxfor 25 minutes. After concentrating the reaction mixture under reducedpressure, water and potassium carbonate were added to the residuefollowed by the extraction with methylene chloride. Next, it was driedover anhydrous sodium sulfate and concentrated under reduced pressure tothereby give 802 mg of the title compound as a slightly yellow oilysubstance.

¹H-NMR(CDCl₃) δ ppm; 1.26(t, J=7.1 Hz, 3H), 1.28(s, 6H), 1.54-1.65(m,3H), 1.76-2.22(m, 7H), 2.98-3.16(m, 4H), 4.11(q, J=7.1 Hz, 2H)

Production Example 90(anti)-2-(3-Azabicyclo[3.3.1]non-9-yl)-2-methyl-1-propanol

250 mg of lithium aluminum hydride was suspended in tetrahydrofuran (30ml) and ice-cooled. Into this suspension was dropped a solution of 802mg of ethyl (anti)-2-(3-azabicyclo[3.3.1]non-9-yl)-2-methylpropionate intetrahydrofuran (10 ml) and the resulting mixture was stirred for 30minutes. By successively adding 0.25 ml of water, 0.25 ml of 15% sodiumhydroxide and 0.75 ml of water, the excessive reagent was decomposed.After further adding anhydrous sodium sulfate and celite, the reactionmixture was stirred at room temperature. Then the reaction mixture wasfiltered and concentrated to thereby give 757 mg of the title compoundas a slightly yellow oily substance.

¹H-NMR(CDCl₃) δ ppm; 1.01(s, 6H), 1.59-1.71(m, 4H), 1.82-2.06(m, 6H),2.14(m, 1H), 3.01-3.07(m, 2H), 3.09-3.14(m, 2H), 3.42(s, 2H)

Production Example 91 (anti)-2-(3-Azabicyclo[3.3.1]non-9-yl)-1-propanol

The title compound was obtained as a colorless oily substance from ethyl(anti)-2-(3-azabicyclo[3.3.1]non-9-yl)propionate by the same methods asthose of Example 12 and Production Examples 89 and 90.

¹H-NMR(CDCl₃) δ ppm; 0.97(d, J=6.8 Hz, 3H), 1.36(m, 1H), 1.54-2.26(m,11H), 2.95-3.03(m, 2H), 3.16(m, 2H), 3.46(dd, J=6.4, 10.6 Hz, 1H),3.71(dd, J=3.3, 10.6 Hz, 1H)

Production Example 92 (syn)-2-(3-Azabicyclo[3.3.1]non-9-yl)ethanol

The title compound was obtained as a colorless oily substance from ethyl(syn)-(3-azabicyclo[3.3.1]non-9-yl)acetate by the same method as the oneof Production Example 90.

¹H-NMR(CDCl₃) δ ppm; 01.50(br.s, 2H), 1.62-1.94(m, 9H), 2.19(m, 1H),2.78-2.86(m, 2H), 3.18-3.25(m, 2H), 3.70(t, J=6.8 Hz, 2H), 3.75(m, 1H)

Production Example 933-Methyl-9-methoxymethylene-3-azabicyclo[3.3.1]nonane

3.67 ml of methoxytrimethylsilane was dissolved in 30 ml oftetrahydrofuran and cooled to −60° C. Next, 18.1 ml of a 1.3 M solutionof sec-butyllithium in cyclohexane was dropped thereinto whilemaintaining the bulk temperature at −50° C. or below. After thecompletion of the dropping, the resulting mixture was stirred at −25 to−30° C. for 30 minutes. Then it was cooled to −35° C. and a solution of3.0 g of 3-methyl-3-azabicyclo[3.3.1]nonan-9-one in tetrahydrofuran (10ml) was dropped thereinto while maintaining the bulk temperature at −25°C. or below. Subsequently, the reaction mixture was slowly heated toroom temperature. After stirring for 6 hours, a saturated aqueoussolution of ammonium chloride was added to the reaction mixture followedby the extraction with ethyl acetate. The ethyl acetate layer was washedwith water and a saturated aqueous solution of sodium chloride, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. Thus 4.96 g of a pale yellow oily substance was obtained.

3.91 g of this oily substance was dissolved in tetrahydrofuran (50 ml).After adding 3.01 g of 35% potassium hydride, the resulting mixture wasstirred at 60° C. for 30 minutes. Then a saturated aqueous solution ofammonium chloride was added to the reaction mixture followed by theextraction with ethyl acetate. The ethyl acetate layer was washed withwater and a saturated aqueous solution of sodium chloride, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Thenthe residue was purified by silica gel column chromatography (elutedwith n-hexane/ethyl acetate) to thereby give 1.14 g of the titlecompound as a colorless oily substance.

¹H-NMR(CDCl₃) δ ppm; 1.46(m, 1H), 1.54-1.74(m, 3H), 1.79-1.91(m, 2H),2.06-2.21(br.m, 5H), 2.58(m, 1H), 2.82-2.95(m, 3H), 3.54(s, 3H), 5.80(s,1H)

Production Example 94[(anti)-(3-Methyl-3-azabicyclo[3.3.1]non-9-yl)methyl]acetate

To 1.14 g of 3-methyl-9-methoxymethylene-3-azabicyclo[3.3.1]nonane wereadded 10 ml of 1 N hydrochloric acid and 20 ml of methanol and theresulting mixture was stirred at room temperature for 2 hours. Afteradding 5 ml of conc. hydrochloric acid, the resulting mixture wasstirred for additional 16 hours. After adding an aqueous solution ofpotassium carbonate, the reaction mixture was extracted with ethylacetate. The ethyl acetate layer was washed with water and a saturatedaqueous solution of sodium chloride, dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (eluted with n-hexane/ethyl acetate) tothereby give 450 mg of a colorless oily substance.

150 mg of lithium aluminum hydride was suspended in tetrahydrofuran (10ml) and ice-cooled. Then 450 mg of the above-mentioned oily substancedissolved in tetrahydrofuran (5 ml) was dropped thereinto and theresulting mixture was stirred for 2 hours. Next, 0.15 ml of water, 0.15ml of 15% sodium hydroxide and 0.45 ml of water were successively addedthereto to thereby decompose the excessive reagent. After further addinganhydrous sodium sulfate and celite, the reaction mixture was stirred atroom temperature. Then the reaction mixture was filtered andconcentrated to thereby give 500 mg of a colorless oily substance.

500 mg of this oily substance was dissolved in methylene chloride (10ml) and 0.5 ml of triethylamine, 0.34 ml of acetic anhydride and acatalytic amount of 4-dimethylaminopyridine were added thereto. Theobtained mixture was stirred at room temperature for 2 hours. Then thereaction mixture was concentrated and a saturated aqueous solution ofsodium hydrogencarbonate was added thereto followed by the extractionwith ethyl acetate. The ethyl acetate layer was washed with water and asaturated aqueous solution of sodium chloride, dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluted with n-hexane/ethylacetate) to thereby give 149 mg of the title.compound as a colorlessoily substance.

¹H-NMR(CDCl₃) δ ppm; 1.42(m, 1H), 1.51-1.61(m, 2H), 1.65-1.79(m, 5H),2.06(s, 3H), 2.10-2.21(m, 5H), 2.44(m, 1H), 2.88-2.95(m, 2H), 4.23(d,J=7.3 Hz, 2H)

Production Example 95[(anti)-[3-(Vinyloxycarbonyl)-3-azabicyclo[3.3.1]non-9-yl]methyl]acetate

168 mg of [(anti)-(3-methyl-3-azabicyclo[3.3.1]non-9-yl)methyl]acetatewas dissolved in 1,2-dichloroethane (5 ml). After adding 1 ml of vinylchloroformate, the resulting mixture was stirred at room temperature for35 minutes and then heated under reflux for 5 hours. Then the reactionmixture was concentrated under reduced pressure and the residue waspurified by silica gel column chromatography (eluted with n-hexane/ethylacetate) to thereby give 101 mg of the title compound as a white solid.

¹H-NMR(CDCl₃) δ ppm; 1.49(m, 1H), 1.60-1.90(m, 7H), 2.00(m, 1H), 2.08(s,3H), 3.11(m, 1H), 3.19(m, 1H), 4.18-4.30(m, 4H), 4.46(dd, J=1.5, 6.2 Hz,1H), 4.79(dd, J=1.5, 14.1 Hz, 1H), 7.25(dd, J=6.2, 14.1 Hz, 1H)

Production Example 96(anti)-[3-[Vinyloxycarbonyl)-3-azabicyclo[3.3.1]non-9-yl]methanol

101 mg of[(anti)-[3-(vinyloxycarbonyl)-3-azabicyclo-[3.3.1]non-9-yl]methyl]acetatewas dissolved in methanol (3 ml). After adding 1 ml of 1 N sodiumhydroxide, the resulting mixture was stirred at room temperature for 1hour. Then the reaction mixture was concentrated under reduced pressureand, after adding water, extracted with ethyl acetate. The ethyl acetatelayer was washed with a saturated aqueous solution of sodium chloride,dried over anhydrous sodium sulfate and concentrated under reducedpressure to thereby give 91 mg of the title compound as a colorless oilysubstance.

¹H-NMR(CDCl₃) δ ppm; 1.36-1.96(m, 10H), 3.12(m, 1H), 3.19(m, 1H),3.83(d, J=7.5 Hz, 2H), 4.19-4.27(m, 2H), 4.45(dd, J=1.5, 6.2 Hz, 1H),4.79(dd, J=1.5, 13.9 Hz, 1H), 7.25(dd, J=6.2, 13.9 Hz, 1H)

Production Example 97(anti)-3-(Vinyloxycarbonyl)-3-azabicyclo[3.3.1]nonan-9-ol and(syn)-3-(vinyloxycarbonyl)-3-azabicyclo[3.3.1]nonan-9-ol

The title compounds were obtained from(3-methyl-3-azabicyclo[3.3.1]non-9-yl)acetate by the same methods asthose of Production Examples 95 and 96.

¹H-NMR(CDCl₃) δ ppm; 1.46(m, 1H), 1.57-1.77(m, 4H), 1.84-1.92(m, 2H),1.97-2.12(m, 2H), 3.14(m, 1H), 3.22(m, 1H), 3.93(t, J=3.5 Hz, 1H),4.20-4.30(m, 2H), 4.46(dd, J=2.1, 6.2 Hz, 1H), 4.79(dd, J=2.1, 13.9 Hz,1H), 7.23(dd, J=6.2, 13.9 Hz, 1H)

¹H-NMR(CDCl₃) δ ppm; 1.42(m, 1H), 1.56-1.75(m, 4H), 1.80-1.99(m, 4H),3.44(m, 1H), 3.53(m, 1H), 3.83(t, J=3.5 Hz, 1H), 3.88-3.98(m, 2H),4.44(dd, J-1.5, 6.3 Hz, 1H), 4.78(dd, J=1.5, 13.9 Hz, 1H), 7.25(dd,J=6.3, 13.9 Hz, 1H)

Example 124(anti)-2-[3-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]non-9-yl]ethanol

To 348 mg of(anti)-2-[3-(vinyloxycarbonyl)-3-azabicyclo-[3.3.1]non-9-yl]ethanol wasadded 5 ml of 4 N hydrogen chloride in dioxane and the resulting mixturewas stirred at room temperature for 1 hour. Then it was concentratedunder reduced pressure and 20 ml of methanol was added to the residue.After heating under reflux for 1 hour, the reaction mixture wasconcentrated under reduced pressure to thereby give crude(anti)-2-(3-azabicyclo[3.3.1]non-9-yl)ethanol hydrochloride as a whitesolid. Next, 5 ml of N,N-dimethylformamide was added thereto. Afterfurther adding 374 mg of8-chloromethyl-10H-pyrazino[2,3-b][1,4]benzothiazine and 622 mg ofanhydrous potassium carbonate, the resulting mixture was stirred at 80°C. for 4 hours. Then ice/water was added to the reaction mixturefollowed by the extraction with ethyl acetate. The ethyl acetate layerwas washed with water and a saturated aqueous solution of sodiumchloride, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluted with methylene chloride/methanol) to thereby give341 mg of the title compound as a dark yellow powder.

¹H-NMR(CDCl₃) δ ppm; 1.33(m, 1H), 1.44-1.85(m, 10H), 2.18-2.26(m, 2H),2.55(m, 1H), 2.89-2.95(m, 2H), 3.22(s, 2H), 3.69(q, J=6.8 Hz, 2H),6.52(br.s 2H), 6.78(dd, J=1.5, 7.9 Hz, 1H), 6.83(d, J=7.9 Hz, 1H),7.57(d, J=2.9 Hz, 1H), 7.69(d, J=2.9 Hz, 1H)

MS: FAB(+)383(MH⁺)

m.p. 123-127° C.

Examples 125 to 128

The following compounds were obtained by the same method as the one ofExample 124.

TABLE 48 Ex. Structural formula MS M.p. NMR 125

FAB(+) 475(MH⁺) 215- 219° C. ¹H-NMR(CDCl₃) δ ppm: 1.45-1.79(m, 8H),2.16- 2.23(m, 2H), 2.56(m, 1H), 2.82(s, 6H), 2.92- 2.99(m, 2H), 3.19-3.26(m, 4H), 4.16(m, 1H), 6.51(d, J=1.5Hz, 1H), 6.57(br.s, 1H), 6.77(dd,J=1.5, 8.1Hz, 1H), 6.83(d, J=8.1Hz, 1H), 7.56(d, J=2.9Hz, 1H), 7.69(d,J=2.9Hz, 1H) 126

FAB(+) 355(MH⁺) 215- 219° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.30-1.41(m, 3H),1.60- 1.66(m, 2H), 1.90- 2.03(m, 2H), 2.13- 2.20(m, 2H), 2.52(m, 1H),2.79-2.88(m, 2H), 3.15(s, 2H), 3.53(m, 1H), 4.62(d, J=2.9Hz, 1H),6.70(dd, J=1.3, 7.9Hz, 1H), 6.73(d, J=1.3Hz, 1H), 6.84(d, J=7.9Hz, 1H),7.63(d, J=2.9Hz, 1H), 7.64(d, J=2.9Hz, 1H), 9.56(s, 1H) 127

FAB(+) 355(MH⁺) 189- 192° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.34(m, 1H), 1.52-1.68(m, 4H), 1.72- 1.80(m, 2H), 2.43- 2.62(m, 5H), 3.14(s, 2H), 3.49(m,1H), 4.57(d, J=2.6Hz, 1H), 6.69(dd, J=1.3, 7.9Hz, 1H), 6.73(d, J=1.3Hz,1H), 6.83(d, J=7.9Hz, 1H), 7.63(d, J=2.9Hz, 1H), 7.64(d, J=2.9Hz, 1H),9.55(s, 1H) 128

FAB(+) 368(MH⁺) 233- 236° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.36-1.58(m, 4H),1.60- 1.75(m, 4H), 2.08-2.16(m, 2H), 2.56(m, 1H), 2.35-2.42(m, 2H),3.18(s, 2H), 3.52(dd, J=5.7, 7.3Hz, 2H), 4.37(t, J=5.7Hz, 1H), 6.71(dd,J=1.5, 7.9Hz, 1H), 6.74(d, J=1.5Hz, 1H), 6.85(d, J=7.9Hz, 1H), 7.63(d,J=2.9Hz, 1H), 7.64(d, J=2.9Hz, 1H), 9.57(s, 1H)

Example 129(anti)-(6R*,8R*)-[3-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-6,8-dimethyl-3-azabicyclo[3.3.1]non-9-yl]ethanol

To a solution of 2.0 g of(anti)-(6R*,8R*)-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-6,8-dimethyl-3-azabicyclo[3.3.1]non-9-yl]acetatein tetrahydrofuran were added 0.08 ml of triethylamine and 0.05 ml ofethyl chloroformate and the resulting mixture was stirred at roomtemperature for 30 minutes. After adding an aqueous solution of 0.05 gof sodium borohydride, the reaction mixture was stirred at roomtemperature for 30 minutes. Then the reaction mixture was washed withwater and the organic layer was dried over anhydrous magnesium sulfate.After distilling off the solvent under reduced pressure, the residue waspurified by silica gel column chromatography (eluted with methylenechloride/methanol) to thereby give 0.16 g of the title compound as ayellow amorphous substance.

¹H-NMR(CDCl₃) δ ppm; 100(d, J=7.2 Hz, 6H), 1.37-1.80(m, 10H), 1.97(d,J=8.0 Hz, 2H), 2.59(d, J=8.0 Hz, 2H), 3.26(s, 2H), 3.60-3.70(m, 2H),6.38(br.s, 1H), 6.52(s, 1H), 6.77(d, J=8.0 Hz, 1H), 6.82(d, J=8.0 Hz,1H), 7.5,6(d, J=2.8 Hz, 1H), 7.68(d, J=2.8 Hz, 1H)

MS: FAB(+)411(MH⁺)

Example 130(anti)-1-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]non-9-yl]-2-methyl-2-propanol

To 10 ml of N,N-dimethylformamide were added 790 mg of8-chloromethyl-10H-pyrazino[2,3-b][1,4]benzothiazine, 740 mg of(anti)-1-(3-azabicyclo[3.3.1]non-9-yl)-2-methyl-2-propanol hydrochlorideand 1.31 g of anhydrous potassium carbonate and the resulting mixturewas stirred at 80° C. for 3.5 hours. After adding ice/water, thereaction mixture was extracted with ethyl acetate. The ethyl acetatelayer was washed with water and a saturated aqueous solution of sodiumchloride, dried over anhydrous sodium sulfate and concentrated underreduced pressure. Then the residue was purified by silica gel columnchromatography (eluted with toluene/ethyl acetate) to thereby give 568mg of the title compound as a yellow powder.

¹H-NMR(CDCl₃) δ ppm; 1.24(s, 6H), 1.38-1.56(m, 3H), 1.58-1.70(m, 6H),1.74-1.86(m, 2H), 2.24-2.30(m, 2H), 2.55(m, 1H), 2.87-2.94(m, 2H),3.22(s, 2H), 6.52(d, J=1.5 Hz, 1H), 6.59(br.s, 1H), 6.78(dd, J=1.5, 7.9Hz, 1H), 6.83(d, J=7.9 Hz, 1H), 7.56(d, J=2.9 Hz, 1H), 7.69(d, J=2.9 Hz,1H)

MS: FAB(+)411(MH⁺)

m.p.: 182-185° C.

Examples 131 to 133

The following compounds were obtained by the same method as the one ofExample 130.

TABLE 49 Ex. Structural formula MS M.p. NMR 131

FAB (+) 411 (MH⁺) 181- 183° C. ¹H-NMR (DMSO-d₆) δ ppm: 0.91(s, 6H),1.34-1.54(m, 4H), 1.80-1.94(m, 4H), 2.12-2.20(m, 2H), 2.60(m, 1H),2.79-2.86 (m, 2H), 3.16(m, 4H), 4.49(t, J=5.1Hz, 1H), 6.70(dd, J=1.5,7.9Hz, 1H), 6.73(d, J=1.5Hz, 1H), 6.84(d, J=7.9Hz, # 1H), 7.63(d,J=2.7Hz, 1H), 7.64(d, J=2.7Hz, 1H), 9.56(s, 1H) 132

FAB (+) 397 (MH⁺) 88- 92° C. ¹H-NMR (CDCl₃) δ ppm: 0.97(d, J=6.8Hz, 3H),1.19(m, 1H), 1.35(t, J=5.4Hz, 1H), 1.43- 1.55(m, 3H), 1.66-1.84(m, 4H),1.97(m, 1H), 2.13-2.22(m, 2H), 2.56(m, 1H), 2.88-2.98(m, 2H), 3.21(s,2H), 3.48(m, 1H), 3.52(m, 1H), 6.52(br.s, 1H), 6.60(br.s, 1H), #6.78(dd, J=1.5, 7.9Hz, 1H), 6.83(d, J=7.9Hz, 1H), 7.56(d, J=2.7Hz, 1H),7.69(d, J=2.7Hz, 1H) 133

FAB (+) 368 (MH⁺) 171- 173° C. ¹H-NMR (CDCl₃) δ ppm: 1.40(br.t, J=4.9Hz,1H), 1.49-1.75(m, 8H), 1.76-1.86(m, 2H), 2.38-2.46(m, 2H), 2.55- 2.69(m,3H), 3.21(s, 2H), 3.68(q, J=6.8Hz, 2H), 6.50(br.s, 1H), 6.59(br.s, 1H),6.77(br.d, J= 7.7Hz, 1H), 7.82(d, J=7.7Hz, 1H), 7.57(d, J= # 2.9Hz, 1H),7.69(d, J=2.9Hz, 1H)

Production Example 98 4-[(3-Chloropyrazin-2-yl)thio]-3-nitrobenzylalcohol

1.876 g of 4-chloro-3-nitrobenzyl alcohol was dissolved in 20 ml ofdimethyl sulfoxide. After adding 820 mg of anhydrous sodium sulfide, theresulting mixture was stirred at room temperature for 15 hours. Afteradding 1.19 g of 2,3-dichloropyrazine thereto, the reaction mixture wasstirred at 100° C. for 1 hour. After adding ice/water, the reactionmixture was extracted with ethyl acetate, washed successively withwater, 1 N hydrochloric acid, water, 1 N sodium hydroxide, and asaturated aqueous solution of sodium chloride and dried over anhydrousmagnesium sulfate. After distilling off the solvent under reducedpressure, the residue was purified by silica gel column chromatography(eluted with ethyl acetate/n-hexane) to thereby give 1.60 g of the titlecompound as yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 4.46(d, J=5.9 Hz, 2H), 5.61(t, J=5.9 Hz, 1H),7.70(dd, J=1.8, 8.1 Hz, 1H), 7.76(d, J=8.1 Hz, 1H), 8.09(d, J=1.8 Hz,1H), 8.33(d, J=2.6 Hz, 1H), 8.41(d, J=2.6 Hz, 1H)

m.p.: 110-113° C.

Production Example 99 3-Amino-4-[(3-chloropyrazin-2-yl)thio]benzylalcohol

1.60 g of 4-[(3-chloropyrazin-2-yl)thio]-3-nitrobenzyl alcohol wasdissolved in a solvent mixture of tetrahydrofuran (20 ml)/2-propanol (20ml)/water (7 ml). After adding 0.16 g of ammonium chloride and 1.50 g ofiron powder, the resulting mixture was heated under reflux for 30minutes. Then the reaction mixture was filtered through celite andconcentrated under reduced pressure. After adding ethanol, the reactionmixture was concentrated under reduced pressure. Then tetrahydrofuranwas added to the residue and the insoluble matters were separated byfiltration. After distilling off the solvent under reduced pressure,1.47 g of the title compound was obtained as yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 4.41(d, J=5.9 Hz, 2H), 5.16(t, J=5.9 Hz, 1H),5.38(br.s, 2H), 6.51(dd, J=1.8, 7.9 Hz, 1H), 6.77(d, J=1.8 Hz, 1H),7.18(d, J=7.9 Hz, 1H), 8.17(d, J=2.6 Hz, 1H), 8.34(d, J=2.6 Hz, 1H)

m.p.: 148-150° C. (decompose)

Production Example 100 Methyl3-amino-4-(4-cyanopyridin-3-yl)thiobenzoate

To a solution of 34.8 g of methyl 3-amino-4-mercaptobenzoate in degasseddimethylformamide (150 ml) was added 11.7 g of sodium hydride at 10° C.or below in a nitrogen atmosphere. After stirring for 20 minutes, 16.86g of 3-chloro-4-cyanopyridine was added thereto and the resultingmixture was stirred for additional 20 minutes. After adding ethylacetate, the mixture was washed with water and the aqueous layer wasextracted with ethyl acetate. The organic layers were combined, washedwith water and a saturated aqueous solution of sodium chloride, driedover anhydrous magnesium sulfate, filtered and concentrated underreduced pressure. The solid matter precipitated during the aboveprocedure was taken up by filtration and washed with ether. Thus, 23.1 gof the title compound was obtained as a yellow solid.

¹H-NMR(CDCl₃) δ ppm: 3.92(s, 3H), 4.46(br.s, 2H), 7.41(dd, J=2,8 Hz,1H), 7.46(dd, J=1,5 Hz, 1H), 7.49(d, J=2 Hz, 1H), 7.53(d, J=8 Hz, 1H),8.20(d, J=1 Hz, 1H), 8.51(d, J=5 Hz, 1H)

Production Example 101 Methyl3-amino-4-(1-oxo-4-cyano-3-pyridylthio)benzoate

To a solution of 9.33 g of methyl 3-amino-4-mercaptobenzoate indimethylformamide (50 ml) was added 2.04 g of sodium hydride at 0° C. ina nitrogen atmosphere. After stirring for 30 minutes, a solution of 5.25g of 3-chloro-4-cyanopyridine oxide in N,N-dimethylformamide (20 ml) wasadded thereto and the resulting mixture was stirred for additional 2hours. After diluting with ethyl acetate, the mixture was washed withwater, dried over anhydrous magnesium sulfate, filtered and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (eluted with dichloromethane/methanol) to thereby give0.85 g of the title compound as a pale yellow solid.

¹H-NMR(DMSO-d₆) δ ppm: 3.83(s, 3H), 6.07(br.s, 2H), 7.14(dd, J=2,8 Hz,1H), 7.20(d, J=2 Hz, 1H), 7.48(d, J=2 Hz, 1H), 7.49(d, J=8 Hz, 1H),7.94(d, J=7 Hz, 1H), 8.16(d, J=2,7 Hz, 1H)

Production Example 102 4-Chloro-5-nitro-o-anisic acid

To a solution of 33 g of 4-chloro-o-anisic acid in sulfuric acid (100ml) was added 20 g of potassium nitrate under ice-cooling and theresulting mixture was stirred for 2 hours. The reaction mixture wasadded to ice/water and extracted with ethyl acetate and the organiclayer was dried over anhydrous magnesium sulfate. After distilling offthe solvent under reduced pressure, 41 g of the title compound wasobtained as pale yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 3.96(s, 3H), 7.49(s, 1H), 8.38(s, 1H)

Production Example 103 Methyl 4-mercapto-5-nitro-o-anisate

To a solution of 3.1 g of 4-chloro-5-nitro-o-anisic acid in methanol(100 ml) was added a catalytic amount of sulfuric acid and the resultingmixture was heated under reflux for 3 hours. Then the reaction mixturewas poured into ice/water and extracted with ethyl acetate. The organiclayer was washed with a saturated aqueous solution of sodium chlorideand dried over anhydrous magnesium sulfate. After distilling off thesolvent under reduced pressure, 3.3 g of methyl4-chloro-5-nitro-o-anisate was obtained as pale yellow crystals.

To a solution of 3.3 g of the crystals obtained above in methanol (50ml) was added 3.2 g of sodium hydrogensulfide and the resulting mixturewas heated under reflux for 30 minutes. After distilling off the solventunder reduced pressure, dilute hydrochloric acid was added to theresidue followed by extraction with ethyl acetate and the organic layerwas then dried over anhydrous magnesium sulfate. After distilling offthe solvent under reduced pressure, diethyl ether was added to theresidue and the crystals thus precipitated were taken up by filtration.Thus 2.1 g of the title compound was obtained as yellow crystals.

¹H-NMR(CDCl₃) δ ppm: 3.91(s, 3H), 4.00(s, 3H), 4.28(s, 1H), 6.89(s, 1H),8.81(s, 1H)

Production Example 104 Methyl2-methoxy-4-(2-chloropyrazin-3-yl)thio-5-nitrobenzoate

To a solution of 6.45 g of methyl 4-mercapto-5-nitro-o-anisate inN,N-dimethylformamide (100 ml) were added 4.4 g of potassium carbonateand 4.75 g of 2,3-dichloropyrazine. Then the mixture was allowed toreact at 80° C. for 2 hours. After adding ethyl acetate, the reactionmixture was washed with a saturated aqueous solution of sodium chlorideand the organic layer was dried over anhydrous magnesium sulfate. Afterdistilling off the solvent under reduced pressure, the residue waspurified by silica gel column chromatography (eluted with n-hexane/ethylacetate) to thereby give 3.14 g of the title compound as a brown solid.

¹H-NMR(CDCl₃) δ ppm: 3.93(s, 3H), 3.94(s, 3H), 7.16(s, 1H), 8.19(d,J=2.4 Hz, 1H), 8.23(d, J=2.4 Hz, 1H), 8.71(s,1H)

Production Example 105 Methyl 5-amino-6-mercaptonicotinate

To a solution of 6 g of methyl 6-chloro-5-nitronicotinate in methanol(100 ml) was added 6.7 g of sodium hydrogensulfide and the resultingmixture was heated under reflux for 2 hours. After distilling off thesolvent under reduced pressure, dilute hydrochloric acid was added tothe residue followed by extraction with ethyl acetate. The organic layerwas dried over anhydrous magnesium sulfate and the solvent was distilledoff under reduced pressure. Diisopropyl ether was added to the residueand the crystals thus precipitated were taken up by filtration tothereby give 24.7 g of the title compound as yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 3.78(s, 3H),5.91-6.00(br.s, 2H), 7.12(d, J=2.0Hz, 1H), 7.53(dd, J=2.0, 6.4 Hz, 1H)

Production Example 106 Diethyl4-(methoxymethoxy)cyclohexane-1,1-dicarboxylate

12.3 g of diethyl 4-hydroxycyclohexane-1,1-dicarboxylate was dissolvedin 160 ml of dichloromethane and 26.3 ml of diisopropylethylamine wasadded thereto followed by ice-cooling. Next, 9.6 ml of chloromethylmethyl ether was added thereto and the reaction mixture was stirred atroom temperature for 15 hours. Then the reaction mixture wasconcentrated and the residue was purified by silica gel columnchromatography (eluted with n-hexane/ethyl acetate) to thereby give11.10 g of the title compound as a colorless oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.24(t, J=7.1 Hz, 3H), 1.26(t, J=7.1 Hz, 3H),1.51-1.62(m, 2H), 1.81-1.90(m, 4H), 2.25-2.34(m, 2H), 3.36(s, 3H),3.61(m, 1H), 4.17(q, J=7.1 Hz, 2H), 4.20(q, J=7.1 Hz, 2H), 4.66(s, 2H)

Production Example 107 4-(Methoxymethoxy)cyclohexane-1,1-dimethanol

1.76 g of lithium aluminum hydride was suspended in 90 ml oftetrahydrofuran and ice-cooled. Then 11.1 g of diethyl4-(methoxymethoxy)cyclohexane-1,1-dicarboxylate dissolved in 30 ml oftetrahydrofuran was dropped thereinto. After stirring for 40 minutes,1.8 ml of water, 1.8 ml of 15% sodium hydroxide and 5.4 ml of water weresuccessively added thereto so as to decompose the excessive reagent.After further adding anhydrous sodium sulfate and celite, the reactionmixture was stirred at room temperature, filtered and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluted with dichlorometheane/methanol) to thereby give6.84 g of the title compound as a white solid.

¹H-NMR(CDCl₃) δ ppm: 1.17-1.26(m, 2H), 1.44-1.54(m, 2H), 1.66-1.74(m,2H), 1.75-1.84(m, 2H), 2.12(br.s, 2H), 3.37(s, 3H), 3.56(s, 2H), 3.59(m,1H), 3.71(s, 2H), 4.68(s, 2H)

Production Example 108 4-(Methoxymethoxy)cyclohexane-1,1-dimethyldimethanesulfonate

6.84 g of 4-(methoxymethoxy)cyclohexane-1,1-dimethanol was dissolved in110 ml of dichloromethane and 13.56 g of pyridine was added thereto andice-cooled. 7.79 ml of methanesulfonyl chloride was added thereto andthe resulting mixture was stirred at room temperature for 17 hours. Thenthe reaction mixture was concentrated and the residue was purified bysilica gel column chromatography (eluted with n-hexane/ethyl acetate) tothereby give 11.91 g of the title compound as a colorless oilysubstance.

¹H-NMR(CDCl₃) δ ppm: 1.37-1.46(m, 2H), 1.52-1.63(m, 2H), 1.71-1.84(m,4H), 3.05(s, 6H), 3.37(s, 3H), 3.65(m, 1H), 4.10(s, 2H), 4.17(s, 2H),4.66(s, 2H)

Production Example 109 N-Benzyl-cis-1,2,3,6-tetrahydrophthalimide

30.2 g of cis-1,2,3,6-tetrahydrophthalimide was dissolved in 200 ml ofN,N-dimethylformamide. After adding 38.7 g of potassium carbonate and30.4 g of benzyl chloride, the resulting mixture was stirred at 50° C.for 3 hours and further at room temperature overnight. Then the reactionmixture was diluted with ethyl acetate and washed with water. Theaqueous layer was extracted with ethyl acetate. The organic layer waswashed successively with water and a saturated aqueous solution ofsodium chloride and dried over anhydrous magnesium sulfate. Afterfiltering, the solvent was distilled off under reduced pressure. Thecrude crystals thus obtained were ground and washed with diisopropylether and n-hexane followed by filtration. Thus 39.1 g of the titlecompound was obtained as pale yellow crystals.

¹H-NMR(CDCl₃) δ ppm: 2.16-2.29(m, 2H), 2.55-2.68(m, 2H), 3.04-3.15(m,2H), 4.63(s, 2H), 5.83-5.92(m, 2H), 7.22-7.33(m, 5H)

Production Example 110 3-Benzyl-3-azabicyclo[4.3.0]-7-nonene

11.6 g of N-benzyl-cis-1,2,3,6-tetrahydrophthalimide was dissolved in280 ml of tetrahydrofuran. Then 5.47 g of lithium aluminum hydride wasgradually added thereto under ice-cooling. After the completion of theaddition, the resulting mixture was stirred at room temperatureovernight. Into the reaction mixture were successively dropped 6 ml ofwater, 6 ml of a 15% solution of sodium hydroxide and 13 ml of waterunder ice-cooling. The suspended matters thus formed were taken up byfiltration and the mother liquor was dried over anhydrous magnesiumsulfate. After filtration, the solvent was concentrated under reducedpressure and the residue thus obtained was purified by silica gel columnchromatography (eluted with n-hexane/ethyl acetate) to thereby give 8.33g of the title compound as a pale yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.84-1.90(m, 2H), 2.10-2.30(m, 4H), 2.40(br.s, 2H),2.92-2.98(m, 2H), 3.62(s, 2H), 5.81(m, 2H),7.22-7.40(m, 5H)

Production Example 111 N-Methyl-2-(pyridin-4-yl)ethanesulfonamide

To 50 ml of a 40% solution of methylamine in methanol was added 3.0 g of2-(pyridin-4-yl)ethanesulfonyl chloride hydrochloride as such (i.e., asa solid). After stirring for a while at room temperature, a solution of2.1 g of sodium hydrogencarbonate in 15 ml of water was carefully addedthereto. The reaction mixture was concentrated under reduced pressureand the residue was purified by silica gel column chromatography (elutedwith dichloromethane/methanol) to thereby give 1.3 g of the titlecompound as brownish white scaly crystals.

¹H-NMR(CDCl₃) δ ppm: 2.80(d, J=6 Hz, 3H), 3.12(m, 2H), 3.31(m, 2H),4.49(q, J=6 Hz, 1H), 7.18(d, J=6 Hz, 2H), 8.47(d, J=6 Hz, 2H)

Production Examples

The following compounds were obtained by the same procedure as the oneof Production Example 111.

Prodn. Ex. Structural formula NMR 112

¹H-NMR (CDCl₃) δ ppm: 2.87(s, 6H), 3.09- 3.19(m, 4H), 7.16(d, J=6Hz,2H), 8.55(d, J=6Hz, 2H) 113

¹H-NMR (CDCl₃) δ ppm: 3.08-3.21(m, 4H), 3.27(t, J=5Hz, 4H), 3.75(t,J=5Hz, 4H), 7.16(d, J=6Hz, 2H), 8.55(d, J=6Hz, 2H)

Production Example 1143-[4-(tert-Butoxycarbonyl)piperazino]-3-methoxy-3-cyclobutene-1,2-dione

10.05 g of 1-(tert-butoxycarbonyl)piperazine and 7.67 g of3,4-dimethoxy-3-cyclobutene-1,2-dione were dissolved in 180 ml ofethanol and stirred at room temperature for 18 hours. The precipitatethus formed was taken up by filtration to thereby give 6.92 g of thetitle compound as white needles.

¹H-NMR(CDCl₃) δ ppm: 1.48(s, 9H), 3.51-3.57(m, 6H), 3.87(m, 2H), 4.40(s,3H)

Production Example 1154-Amino-3-[4-(tert-butoxycarbonyl)piperazinol-3-cyclobutene-1,2-dione

2.00 g of3-[4-(tert-butoxycarbonyl)piperazino]-3-methoxy-3-cyclobutene-1,2-dionewas dissolved in 25 ml of methanol. After adding 0.43 g of ammoniumchloride, the resulting mixture was stirred at room temperature for 65hours. The precipitate thus formed was taken up by filtration and washedwith ethanol to thereby give 1.83 g of the title compound as a slightlyyellow powder.

¹H-NMR(DMSO-d₆) δ ppm: 1.42(s, 9H), 3.42(m, 4H), 3.63(m, 4H), 7.73(br.s,2H)

Production Examples

The following compounds were obtained by the same procedure as the oneof Production Example 115.

Prodn. Ex. Structural formula NMR 116

¹H-NMR (DMSO-d₆) δ ppm: 1.41(s, 9H), 3.17(s, 3H), 3.39-3.44(m, 4H),3.57-3.64(m, 4H), 7.65(m, 1H) 117

¹H-NMR (DMSO-d₆) δ ppm: 1.39(s, 9H), 3.14(s, 6H), 3.39-3.44(m, 4H),3.52-3.57(m, 4H)

Production Example 118(4-Diethylphosphono-3-oxo-2-methylbutan-2-yl)acetate

Into a solution of 3.04 g of diethyl methylphosphonate intetrahydrofuran (20 ml) was dropped a 1.6 M solution (12.5 ml) ofn-buthyllithium in hexane at −70° C. in a nitrogen atmosphere. Afteradding 4.00 g of anhydrous cuprous iodide, the reaction mixture washeated to −35° C. and stirred for 30 minutes. After cooling to −70° C.again, the solution was added to a solution of 4.93 g of2-acetoxy-2-methylpropanoyl chloride in tetrahydrofuran (30 ml) whichhad been cooled to −70° C. in a nitrogen atmosphere. Then the internaltemperature was elevated to room temperature and the mixture was stirredfor 15 hours. After adding ethyl acetate, the pH value of the mixturewas regulated to 6 with sodium dihydrogenphosphate. The insolublematters were separated by filtration and the organic layer was driedover anhydrous magnesium sulfate, filtered and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluted with dichloromethane/ethyl acetate) to therebygive 2.61 g of the title compound as a pale yellow oily substance.

¹H-NMR(CDCl₃) δ ppm:

1.33(t, J=7 Hz, 6H), 1.52(s, 6H), 2.08(s, 3H), 3.14(d, J=21 Hz, 2H),4.16(m, 4H)

Production Example 119 Ethyl[4-(ethoxycabronyl)-1-(nitromethyl)cyclohex-1-yl]acetate

1.28 g of anhydrous potassium carbonate was suspended in 9 ml ofdimethyl sulfoxide and heated to 90° C. Then 4.43 g of ethyl[4-(ethoxycarbonyl)cyclohexylidene]acetate and 1.5 ml of nitromethanedissolved in 5 ml of dimethyl sulfoxide were dropped thereinto over 2hours. After heating for 2 hours and 15 minutes, the reaction mixturewas ice-cooled and 3 ml of conc. hydrochloric acid was droppedthereinto. After adding water, it was extracted with ethyl acetate. Theorganic layer was washed successively with water and a saturated aqueoussolution of sodium chloride and dried over anhydrous sodium sulfate.Then it was concentrated under reduced pressure and the residue waspurified by silica gel column chromatography (eluted with n-hexane/ethylacetate). Thus 4.72 g of the title compound was obtained as a slightlyyellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.23-1.30(m, 6H), 1.35-1.45(m, 2H), 1.61-1.76(m,2H), 1.80-1.93(m, 4H), 2.25-2.38(m, 1H), 2.47 and 2.60(s, total 2H),4.10-4.19(m, 4H), 4.64 and 4.80(s, total 2H)

Example 134(anti)-[3-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]non-9-yl]aceticacid methanesulfonate

30.00 g of(anti)-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]non-9-yl]aceticacid was dissolved in 900 ml of tetrahydrofuran. After adding dropwise5.16 ml of methanesulfonic acid thereinto, the resulting mixture wasstirred at room temperature for 2 hours. The precipitate was cillectedby filtration, washed with tetrahydrofuran and hot-air dried at 80° C.for 6 hours to thereby give 37.7 g of a yellow powder.

This powder was dissolved in a mixture of 200 ml of water with 0.49 mlof methanesulfonic acid and the insoluble matter was separated byfiltration. After concentrating under reduced pressure, seed crystalswere added and the mixture was allowed to stand at room temperature for4 days. After adding 50 ml of cold water, the mixture was well groundand collected by filtration. Then it was washed with 30 ml of coldwater, hot-air dried at 80° C. for 10 hours and ground in an agatemortar to thereby give 32.30 g of the title compound as a yellow powder.

¹H-NMR(CD₃OD) δ ppm: 1.65-1.82(m, 4H), 1.87-2.00(m, 2H), 2.07(br.m, 2H),2.28(m, 1H), 2.57(d, J=7.5 Hz, 2H), 2.73(s, 3H), 3.29-3.37(m, 2H),3.52-3.60(m, 2H), 4.17(s, 2H), 6.83(br.s, 1H), 6.95(d, J=8.0 Hz, 1H),6.97(dd, J=1.5, 8.0 Hz, 1H), 7.60(d, J=2.9 Hz, 1H), 7.61(d, J=2.9 Hz,1H)

m.p.: 263-265° C.

Example 135(anti)-[3-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]non-9-yl]aceticacid hydrochloride

10.00 g of(anti)-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]non-9-yl]aceticacid was dissolved in 300 ml of tetrahydrofuran and the insoluble matterwas separated by filtration. After adding 27.8 ml of 1 N hydrochloricacid, the resulting mixture was allowed to stand at room temperature for2 hours. The precipitate thus formed was collected by filtration, washedwith tetrahydrofuran and hot-air dried at 80° C. for 3 hours to therebygive 11.19 g of a yellow powder.

These crystals were added to a mixture of 1.7 l of water with 25.8 ml of1 N hydrochloric acid and dissolved therein by heating. The insolublematter was separated by filtration. After adding seed crystals, themixture was allowed to stand at 4° C. for 20 hours. The precipitate thusformed was collected by filtration, washed with cold water and hot-airdried at 80° C. for 8 hours to thereby give 8.98 g of the title compoundas yellow needles.

¹H-NMR(CD₃OD) δ ppm: 1.63-2.00(m, 6H), 2.06(br.m, 2H), 2.26(m, 1H),2.57(d, J=7.7 Hz, 2H), 3.25-3.36(m, 2H), 3.48-3.58(m, 2H), 4.15(s, 2H),6.83(s, 1H), 6.97(s, 2H), 7.61(s, 2H)

m.p.: 271-276° C. (decomposes)

Example 136(anti)-[3-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]non-9-yl]aceticacid p-toluenesulfonate

1.50 g of(anti)-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]non-9-yl]aceticacid was dissolved in 45 ml of tetrahydrofuran and 0.721 g ofp-toluenesulfonic acid monohydrate was added thereto. After stirring theresulting mixture at room temperature for 1.5 hours, the precipitatethus formed was collected by filtration, washed with tetrahydrofuran andhot-air dried at 80° C. for 6 hours to thereby give a yellow powder.

These crystals were suspended in a solvent mixture of 60 ml of waterwith 6 ml of ethanol and allowed to stand at room temperature overnight.The precipitate thus formed was collected by filtration, washed withwater and hot-air dried at 80° C. for 10 hours to thereby give 1.70 g ofthe title compound as yellow needles.

¹H-NMR(CD₃OD) δ ppm: 1.42-1.78(m, 4H), 1.85-1.96(m, 2H), 2.05 (br.m,2H), 2.25(m, 1H), 2.36(s, 3H), 2.56(d, J=7.5 Hz, 2H), 3.27-3.35(m, 2H),3.50-3.58(m, 2H), 4.16(s, 2H), 6.82(s, 1H), 6.95(s, 2H), 7.21-7.25(m,2H), 7.60(d, J=2.9 Hz, 1H), 7.61(d, J=2.9 Hz, 1H), 7.69-7.73(m, 2H)

m.p.: 265-268° C.

Example 137(anti)-[3-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]nonan-9-yl]aceticacid hemil,2-ethanedisulfonate

1.00 g of(anti)-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]non-9-yl]aceticacid was dissolved in 30 ml of tetrahydrofuran and 0.571 g of1,2-ethanedisulfonic acid dehydrate and 60 ml of ethanol were addedthereto. After stirring the resulting mixture at room temperature for 4hours, the precipitate thus formed was collected by filtration, washedwith ethanol, and hot-air dried at 80° C. for 6 hours to thereby give1.419 g of a yellow powder.

2.815 g of these crystals were suspended in 90 ml of water and allowedto stand at room temperature overnight. The precipitate thus formed wascollected by filtration, washed with water and hot-air dried at 80° C.for 10 hours to thereby give 2.202 g of the title compound as yellowneedles.

¹H-NMR(DMSO-d₆) δ ppm: 1.50-1.64(m, 3H), 1.66-1.80(m, 3H), 1.95(br.m,2H), 2.21(m, 1H), 2.45(d, J=7.5 Hz, 2H), 2.65(s, 2H), 3.22-3.31(m, 2H),3.35-3.45(m, 2H), 4.13(s, 2H), 6.87(s, 1H), 7.01(s, 2H), 7.67(d, J=2.7Hz, 1H), 7.68(d, J=2.7 Hz, 1H)

m.p.: 272-279° C. (decomposes)

Example 138 Sodium(anti)-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]non-9-yl]acetate

1.50 g of(anti)-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]non-9-yl]aceticacid was dissolved in a solvent mixture of 45 ml of tetrahydrofuran with45 ml of ethanol. After adding 3.79 ml of 1 N sodium hydroxide, theresulting mixture was filtered. After almost completely distilling offthe solvent under reduced pressure, ethyl acetate was added to theresidue. Then the precipitate thus formed was collected by filtration,washed with ethyl acetate, hot-air dried at 80° C. for 6 hours andair-dried at room temperature to thereby give 1.516 g of the titlecompound as a yellow powder.

¹H-NMR(CD₃OD) δ ppm: 1.42-1.53(m, 3H), 1.66(br.m, 2H), 1.83-1.95(m, 2H),2.02(m, 1H), 2.25-2.31(m, 2H), 2.36(d, J=7.7 Hz, 2H), 2.66(m, 1H),2.90-2.96(m, 2H), 3.21(s, 2H), 6.67(s, 1H), 6.78(s, 2H), 7.54(d, J=2.9Hz, 1H), 7.56(d, J=2.9 Hz, 1H)

m.p.: 270° C. (decomposes)

Example 139 Potassium(anti)-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]non-9-yl]acetate

3.00 g of(anti)-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]non-9-yl]aceticacid was dissolved in a solvent mixture of 45 ml of tetrahydrofuran with45 ml of ethanol. After adding 7.58 ml of 1 N potassium hydroxide, theresulting mixture was filtered. After distilling off the solvent underreduced pressure, ethanol was added to the residue followed byconcentration again. After adding ethyl acetate, the precipitate thusformed was collected by filtration and dried at room temperature underreduced pressure to thereby give 3.26 g of a yellow powder.

3.60 g of these crystals were hot-recrystallized from 36 ml of ethanol.The precipitate thus formed was collected by filtration, washed withethanol, hot-air dried at 50° C. for 5 hours, ground in mortar andhot-air dried at 100° C. for 10 hours. After allowing to stand at roomtemperature, 1.92 g of the title compound was obtained as a yellowpowder.

¹H-NMR(CD₃OD) δ ppm: 1.42-1.54(m, 3H), 1.66(br.m, 2H), 1.83-1.95(m, 2H),2.02(m, 1H), 2.24-2.32(m, 2H), 2.37(d, J=7.7 Hz, 2H), 2.66(m, 1H),2.90-2.96(m, 2H), 3.21(s, 2H), 6.67(s, 1H), 6.78(s, 2H), 7.54(d, J=2.7Hz, 1H), 7.56(d, J=2.7 Hz, 1H)

m.p.: 280° C. (decomposes)

Example 140(syn)-[3-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]non-9-yl]aceticacid hydrochloride

1.5 g of(syn)-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]non-9-yl]aceticacid was dissolved in 80 ml of tetrahydrofuran. After adding 0.35 ml ofconc. hydrochloric acid and 160 ml of acetone, the resulting mixture wasstirred at room temperature for 1 hour. Then about 200 ml of water wasadded and to dissolve the precipitate. After concentrating the solutionunder reduced pressure to about 30 ml, the precipitate was collected byfiltration and dried under reduced pressure at room temperature tothereby give 1.5 g of the title compound as yellow crystals.

¹H-NMR(CD₃OD) δ ppm: 1.76-2.02(m, 6H), 2.08(br.m, 2H), 2.18(m, 1H),2.51(d, J=7.7 Hz, 2H), 3.25-3.40(m, 4H), 4.18(s, 2H), 6.86(d, J=1.3 Hz,1H), 6.97(d, J=8.1 Hz, 1H), 6.99(dd, J=1.3, 8.1 Hz, 1H), 7.61(d, J=2.7Hz, 1H), 7.62(d, J=2.7 Hz, 1H)

m.p.: 238-248° C.

Example 141(syn)-[3-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]non-9-yl]aceticacid methanesulfonate

10.00 g of(syn)-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]non-9-yl]aceticacid was dissolved in 400 ml of tetrahydrofuran and the insoluble matterwas filtered off. Then 1.64 ml of methanesulfonic acid was droppedthereinto and the resulting mixture was stirred at room temperature. 30minutes thereafter, 800 ml of acetone was added and the resultingmixture was stirred for additional 1 hour. The precipitate was collectedby filtration and washed with acetone to thereby give a yellow powder.

This powder was dissolved in 1.3 l of water and the insoluble matter wasfiltered off. The residue was concentrated under reduced pressure toabout 100 ml and the precipitate was collected by filtration, washedwith a small amount of water and hot-air dried at 50° C. for 2 hours.Then it was dried under reduced pressure in a desiccator for 64 hours tothereby give 9.70 g of the title compound as a yellow powder.

¹H-NMR(CD₃OD) δ ppm: 1.74-2.02(m, 6H), 2.07(br.m, 2H), 2.17(m, 1H),2.51(d, J=7.7 Hz, 2H), 2.72(s, 3H), 3.25-3.39(m, 4H), 4.18(s, 2H),6.84(br.s, 1H), 6.96(d, J=8.1 Hz, 1H), 6.98(dd, J=8.1 Hz, 1H), 7.61(s,2H)

m.p.: 267-271° C. (decompose)

Example 142(syn)-[3-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]non-9-yl]aceticacid p-toluenesulfonate

1.3 g of(syn)-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]non-9-yl]aceticacid was dissolved in 80 ml of tetrahydrofuran. After adding 0.62 g ofp-toluenesulfonic acid monohydrate, the mixture was stirred at roomtemperature for 30 minutes. The precipitate was collected by filtrationand dried under reduced pressure.

The crystals were suspended in 5 ml of ethanol and stirred at roomtemperature for 3 hours. After collected by filtration, the product washot-air dried at 50° C. for 8 hours and then air-dried at roomtemperature for 11 hours. Thus 1.4 g of the title compound was obtainedas yellow needles.

¹H-NMR(CD₃OD) δ ppm: 1.72-1.99(m, 6H), 2.06(br.m, 2H), 2.17(m, 1H),2.37(s, 3H), 2.50(d, J=7.7 Hz, 2H), 3.24-3.38(m, 4H), 4.16(s, 2H),6.82(br.s, 1H), 6.97(s, 2H), 7.21-7.25(m, 2H), 7.61(d, J=3.1 Hz, 1H),7.62(d, J=3.1 Hz, 1H), 7.69-7.73(m, 2H)

m.p.: 157° C. (decomposes)

Example 143(syn)-[3-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]non-9-yl]aceticacid sulfate

1.3 g of(syn)-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]non-9-yl]aceticacid was dissolved in 60 ml of tetrahydrofuran. After adding 0.18 ml ofconc. sulfuric acid and 120 ml of acetone, the resulting mixture wasstirred at room temperature for 1 hour. Then water (about 200 ml) wasadded thereto to thereby dissolve the precipitate and the mixture wasconcentrated to about 20 ml under reduced pressure. After adding seedcrystals, the precipitate was collected by filtration to thereby give1.1 g of the title compound as yellow crystals.

¹H-NMR(CD₃OD) δ ppm: 1.73-2.04(m, 6H), 2.08(br.m, 2H), 2.18(m, 1H),2.51(d, J=7.7 Hz, 2H), 3.25-3.40(m, 4H), 4.18(s, 2H), 6.85(d, J=1.3 Hz,1H), 6.97(br.s, 2H), 7.61(s, 2H)

m.p.: 2256° C. (decomposes)

Example 144 Sodium(syn)-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]non-9-yl]acetate

1.310 g of(syn)-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]non-9-yl]aceticacid was suspended in a solvent mixture of 50 ml of tetrahydrofuran with50 ml of ethanol. After adding 3.31 ml of 1 N sodium hydroxide, theresulting mixture was filtered. After distilling off the solvent underreduced pressure, ethanol was added and the solvent was almostcompletely distilled off under reduced pressure. Then the precipitatewas collected by filtration, washed with a small portion of ethanol andhot-air dried at 90° C. for 10 hours. Then it was allowed to stand atroom temperature to thereby give 1.408 g of the title compound as ayellow powder.

¹H-NMR(CD₃OD) δ ppm: 1.50(m, 1H), 1.65-1.86(m, 6H), 2.03(m, 1H), 2.31(d,J=7.7 Hz, 2H), 2.47-2.53(m, 2H), 2.59-2.64(m, 2H), 2.73(m, 1H), 3.22(s,2H), 6.65(s, 1H), 6.77(s, 2H), 7.54(d, J=2.9 Hz, 1H), 7.56(d, J=2.9 Hz,1H)

m.p.: 260° C. (decomposes)

Example 145 Potassium(syn)-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]non-9-yl]acetate

1.310 g of(syn)-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]non-9-yl]aceticacid was suspended in a solvent mixture of 50 ml of tetrahydrofuran with50 ml of ethanol. After adding 3.31 ml of 1 N potassium hydroxide, theresulting mixture was filtered. After distilling off the solvent underreduced pressure, ethanol was added and the mixture was concentratedagain. After adding ethyl acetate, the precipitate was collected byfiltration and hot-air dried at 90° C. for 10 hours. Then it was allowedto stand at room temperature to thereby give 1.566 g of the titlecompound as a yellow powder.

¹H-NMR(CD₃OD) δ ppm: 1.50(m, 1H), 1.65-1.86(m, 6H), 2.03(m, 1H), 2.31(d,J=7.9 Hz, 2H), 2.46-2.54(m, 2H), 2.58-2.65(m, 2H), 2.73(m, 1H), 3.22(s,2H), 6.66(s, 1H), 6.77(s, 2H), 7.54(d, J=2.8 Hz, 1H), 7.56(d, J=2.8 Hz,1H)

m.p.: 272° C. (decomposes)

Example 146 (10H-Pyrazino[2,3-b][1,4]benzothiazin-8-yl)methanol

To 1.47 g of 3-amino-4-[(3-chloropyrazin-2-yl)thio]benzyl alcohol wereadded 20 ml of methanol and 0.45 ml of conc. hydrochloric acid and theresulting mixture was heated under reflux for 30 minutes. Then thereaction mixture was made alkaline by adding ice-water and aqueousammonia. The precipitate was collected by filtration and dried tothereby give 1.23 g of the title compound as yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 4.30(d, J=6.0 Hz, 2H), 5.17(t, J=6.0 Hz, 1H),6.70(d, J=7.9 Hz, 1H), 6.75(s, 1H), 6.83(d, J=7.9 Hz, 1H), 7.61(d, J=2.6Hz, 1H), 7.63(d, J=2.6 Hz, 1H), 9.50(s, 1H)

Example 147 Methyl 10H-pyrazino[2,3-b][1,4]benzoxazine-8-carboxylate

21.3 g of methyl 3-amino-4-hydroxybenzoate and 23 g of2,3-dichloropyrazine were added to 40 ml of dry N,N-dimethylformamideand the resulting mixture was stirred under heating to 160° C. for 6hours. Then the reaction mixture was brought back to room temperatureand the crystals thus precipitated were taken up by filtration andwashed with ethyl acetate. Thus 23 g of the title compound was obtainedas brown crystals.

¹H-NMR(DMSO-d₆) δ ppm: 3.80(s, 3H), 6.86(d, J=8 Hz, 1H), 7.20(d, J=2 Hz,1H), 7.30(dd, J=2, 8 Hz, 1H), 7.30(d, J=3 Hz, 1H), 7.51(d, J=3 Hz, 1H),9.81(s, 1H)

Example 148 Methyl 10H-pyrido[3,2-b][1,4]benzothiazine-8-carboxylate

150 g of methyl 3-amino-4-mercaptobenzoate hydrochloride was suspendedin 200 ml of diphenyl ether and heated to 100° C. After dropping2-chloropyridine thereinto, 10.3 g of iodine was further added and theresulting mixture was reacted at 200° C. for 3 hours. After adding 20 mlof sulfuric acid and 300 ml of methanol at room temperature, theresulting mixture was heated under reflux for 3 hours. Then the reactionmixture was brought back to room temperature and poured into a coldsaturated aqueous solution of sodium bicarbonate. Next, it was extractedwith ethyl acetate, washed with a saturated aqueous solution of sodiumchloride and then dried over anhydrous magnesium sulfate. The extractwas distilled off under reduced pressure and the residue was purified bysilica gel column chromatography (eluted with ethyl acetate/n-hexane) tothereby give 1.3 g of the title compound as yellow crystals.

¹H-NMR(CDCl₃) δ ppm: 3.88(s, 3H), 6.72(dd, J=5, 7 Hz, 1H), 6.84(br.s,1H), 6.95(d, J=8 Hz, 1H), 7.15(dd, J=2, 8 Hz, 1H), 7.17(d, J=2 Hz, 1H),7.47(dd, J=2, 8 Hz, 1H), 7.84(dd, J=2, 5 Hz, 1H)

Example 149 Methyl 5H-pyrido[3,4-b][1,4]benzothiazine-7-carboxylate

To a solution of 18.43 g of methyl3-amino-4-(4-cyanopyridin-3-yl)thiobenzoate in dimethylformamide (70 ml)was added 22.2 g of p-toluenesulfonic acid in a nitrogen atmosphere.Then the resulting mixture was stirred at 120° C. for 2 hours. Then thereaction mixture was cooled to room temperature and the crystals thusprecipitated in the course of cooling were taken up by filtration andwashed with ethyl acetate. Thus 13.5 g of p-toluenesulfonate of thetitle compound was obtained as yellow crystals. A 10.3 g portion of thissalt was suspended in a solution mixture of 50 ml of a saturated aqueoussolution of sodium hydrogencarbonate with 5 ml of tetrahydrofuran andthe suspension was stirred for 20 minutes. The suspended matters weretaken up by filtration, washed successively with water and ether anddried under reduced pressure overnight. Thus, 6.48 g of the titlecompound was obtained as yellow crystals.

¹H-NMR(CDCl₃) δ ppm: 3.79(s, 3H), 6.48(d, J=6 Hz, 1H), 7.04(d, J=8 Hz,1H), 7.21(d, J=1 Hz, 1H), 7.33(dd, J=1, 8 Hz, 1H), 7.87(s, 1H), 7.98(d,J=6 Hz, 1H), 9.26(s, 1H)

Example 150 Methyl4-cyano-10-(methoxyethyl)-10H-pyrido[3,2-b][1,4]-benzothiazine-8-carboxylate

To a solution of methyl 3-amino-4-(1-oxo-4-cyano-3-pyridylthio)benzoatein pyridine (20 ml) was added 5 ml of acetic anhydride and the resultingmixture was stirred for 16 hours. Then the reaction mixture wasconcentrated under reduced pressure and the residue was purified bysilica gel column chromatography (eluted with dichloromethane/ethylacetate) to thereby give 0.45 g of methyl3-acetamido-4-(1-oxo-4-cyano-3-pyridylthio)benzoate as a colorlesssolid. 0.079 g of sodium hydride was added in a nitrogen atmosphere to asolution of 0.45 g of methyl3-acetamido-4-(1-oxo-4-cyano-3-pyridylthio)benzoate inN,N-dimethylformamide (15 ml) and the resulting mixture was stirred for10 minutes. After adding 0.503 g of sulfur, the resulting mixture wasstirred at 130° C. for 15 minutes. The reaction mixture was diluted withwater and the crystals thus precipitated were taken up by filtration andwashed with water. Thus 0.267 g of methyl4-cyano-10H-pyrido[3,2-b][1,4]-benzothiazine-8-carboxylate was obtainedas yellow crystals. To a solution of 0. 267 g of methyl4-cyano-10H-pyrido[3,2-b][1,4]-benzothiazine-8-carboxylate inN,N-dimethylformamide (20 ml) were successively added in a nitrogenatmosphere 0.045 g of sodium hydride and a solution of 0.12 ml ofchloromethyl methyl ether in N,N-dimethylformamide (9 ml) and theresulting mixture was stirred for 1 hour. Then the reaction mixture wasdiluted with water and eluted with ethyl acetate. The organic layer waswashed with water and a saturated aqueous solution of sodium chloride,dried over anhydrous magnesium sulfate, filtered and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluted with n-hexane/dichloromethane) to thereby give0.152 g of the title compound as pale yellow crystals.

¹H-NMR(CDCl₃) δ ppm: 3.40(s, 3H), 3.95(s, 3H), 5.37(s, 2H), 7.22(d, J=8Hz, 1H), 7.26(d, J=5 Hz, 1H), 7.76(dd, J=2, 8 Hz, 1H), 7.77(d, J=2 Hz,1H), 8.19(d, J=5 Hz, 1H)

Example 151 Methyl 10H-pyrazino[2,3-b][1,4]-benzothiazine-7-carboxylate

40 g of methyl 3-(N,N-dimethylcarbamoylthio)-4-nitrobenzoate was addedto a solvent mixture of a 30% aqueous solution of potassium hydroxide(50 ml) with methanol (20 ml) and the resulting mixture was stirredunder heating to 80° C. for 1.5 hours. Then the reaction mixture wasbrought back to room temperature and acidified with dilute hydrochloricacid. The brown crystals thus precipitated were taken up by filtrationand dried. Into a solution of 20 g of the crystals thus obtained and 40g of a tin powder (200-mesh) in ethanol (200 ml) was dropped 10 ml ofconc. hydrochloric acid in such a manner that the temperature in thereaction system did not exceed 70° C. After diluting with methanol, themixture was filtered through celite to thereby eliminate the residualtin. After distilling off the solvent under reduced pressure, ethylacetate saturated with hydrogen chloride gas was added to the oilysubstance thus obtained and the pale yellow crystals thus precipitatedwere filtered. To 15 g of the crystals thus obtained was added 200 ml ofa 10% solution of hydrochloric acid in methanol and the resultingmixture was heated under reflux for 6 hours. After distilling off thesolvent under reduced pressure completely, 30 ml ofN,N-dimethylformamide was added thereto. Next, 15 g of dichloropyrazinewas further added and the resulting mixture was heated to 110° C. for 1hour. After diluting with water, the crystals thus precipitated werefiltered and washed well with water and diethyl ether. Thus 13.5 g ofthe title compound was obtained as yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 3.75(s, 3H), 6.77(d, J=8.4 Hz, 1H), 7.40(d, J=1.8Hz, 1H), 7.53(dd, J=1.8, 8.4 Hz, 1H), 7.68(d, J=2.9 Hz, 1H), 7.69(d,J=2.9 Hz, 1H), 9.93(s, 1H)

Example 152 Methyl 10H-pyrimido[5,4-b][1,4]-benzothiazine-8-carboxylate

100 ml of a solution of 16.3 g of crude methyl3-mercapto-4-aminobenzoate hydrochloride and 20 ml of triethylamine inmethanol was stirred under ice-cooling and 7.2 g of4-chloro-5-bromopyrimidine was dropped thereinto. The colorlessprecipitate thus formed was filtered to thereby give 9.0 g of crudemethyl 4-[5-bromopyrimidin-4-yl)thio]-3-aminobenzoate. 9.0 g of methyl4-[5-bromopyrimidin-4-yl)thio]-3-aminobenzoate, 200 mg of a copperpowder and 1.3 g of potassium carbonate were heated in 5 ml ofN,N-dimethylformamide to 110° C. for 1 hour. Then the mixture washot-filtered to thereby eliminate the copper powder. Afterrecrystallization, the crystals thus precipitated were taken up byfiltration and washed with water to thereby give 6.2 g of the titlecompound as a pale yellow crude product.

¹H-NMR(DMSO-d₆) δ ppm: 3.79(s, 3H), 7.06(d, J=8.5 Hz, 1H), 7.36(d, J=1.1Hz, 1H), 7.37(dd, J=1.1, 8.5 Hz, 1H), 7.89-8.02(br.s, 1H),8.18-8.28(br.s, 1H), 9.43(s, 1H)

Example 153 Methyl7-methoxy-10H-pyrazino[2,3-b][1,4]-benzothiazine-8-carboxylate

To a solution of 2.7 g of methyl2-methoxy-4-(2-chloropyrazin-3-yl)thio-5-nitrobenzoate intetrahydrofuran (100 ml) were added 50 ml of a saturated aqueoussolution of sodium hydrosufide and 30 ml of 27% aqueous ammonia and theresulting mixture was vigorously stirred at room temperature for 1 hour.Then the reaction mixture was extracted with ethyl acetate and theorganic layer was dried over anhydrous magnesium sulfate. Afterdistilling off the solvent under reduced pressure, a solution of theresidue in tetrahydrofuran was stirred at 70° C. for 1 hour. Afterdistilling off the solvent under reduced pressure, dichloroemthane wasadded to the residue. The crystals thus precipitated were filtered tothereby give 1.9 g of the title compound as red crystals.

¹H-NMR(CDCl₃) δ ppm: 3.83(s, 3H), 3.86(s, 3H), 6.36-6.43(br.s, 1H),6.53(s, 1H), 7.00(s, 1H), 7.59(d, J=2.8 Hz, 1H), 7.69(d, J=2.8 Hz, 1H)

Example 154 Methyl10-(methoxymethyl)-10H-pyrazino[2,3-b]pyrido[3,2-e][1,4]thiazine-8-carboxylate

To a solution of 1.0 g of methyl 5-amino-6-mercaptonicotinate inN,N-dimethylformamide (30 ml) were added 0.52 g of sodium hydride (oily:60% or more) and 0.97 g of 2,3-dichloropyrazine and the resultingmixture was reacted at 100° C. for 2 hours. Then ethyl acetate was addedto the reaction mixture, which was then washed with a saturated aqueoussolution of sodium chloride and dried over anhydrous magnesium sulfate.After distilling off the solvent under reduced pressure, diethyl etherwas added to the residue and the crystals thus precipitated were takenup by filtration to thereby give 0.43 g of crude methyl10H-pyrazino[2,3-b]pyrido[3,2-e][1,4]thiazin-8-carboxylate as a brownsolid. To a solution of 1.43 g of these crude crystals inN,N-dimethylformamide (50 ml) were added 0.26 g of sodium hydride (60%oily) and 0.5 g of chloromethyl methyl ether and the resulting mixturewas reacted under ice-cooling for 1 hour. After adding ethyl acetate,the mixture was washed with a saturated aqueous solution of sodiumchloride. The organic layer was dried over anhydrous magnesium sulfate.After distilling off the solvent under reduced pressure, diethyl etherwas added to the residue and the crystals thus precipitated were takenup by filtration to thereby give 1.5 g of the title compound as redcrystals.

¹H-NMR(CDCl₃) δ ppm: 3.52(s, 3H), 3.93(s, 3H), 5.27(s, 2H), 7.78(d,J=1.6 Hz, 1H), 7.82(d, J=2.8 Hz, 1H), 7.85(d, J=2.8 Hz, 1H), 8.58(d,J=1.6 Hz, 1H)

Examples 155 to 157

The following compounds were obtained by the same procedure as the oneof Example 5.

Ex. Structural formula NMR 155

¹H-NMR (DMSO-d₆) δ ppm: 3.33(s, 3H), 3.81(s, 3H), 5.27(s, 2H), 6.97(d,J=8Hz, 1H), 7.41(d, J=2Hz, 1H), 7.46(dd, J=2, 8Hz, 1H), 7.48(d, J=4Hz,1H), 7.69(d, J=4Hz, 1H) 156

¹H-NMR (CDCl₃) δ ppm: 3.56(s, 3H), 3.92(s, 3H), 5.03(s, 2H), 6.88 (d,J=6Hz, 1H), 7.15(d, J=8Hz, 1H), 7.67(m, 2H), 8.18(s, 1H), 8.30(d, J=6Hz,1H) 157

¹H-NMR (CDCl₃) δ ppm: 3.53(s, 3H), 3.87(s, 3H), 3.89(s, 3H), 5.28(s,2H), 6.34(s, 1H), 7.60(s, 1H), 7.84(d, J=2.8Hz, 1H), 7.85(d, J=2.8Hz,1H)

Example 15810-(Methoxymethyl)-10H-pyrazino[2,3-b][1,4]-benzothiazine-7-methanol

100 ml of a solution of 7.0 g of ethyl10H-pyrazino[2,3-b][1,4]benzothiazine-7-carboxylate inN,N-dimethylformamide was ice-cooled in a nitrogen atmosphere and 1.3 gof sodium hydride (60% oily) was added thereto. Then the resultingmixture was brought back to room temperature and stirred for 1 hour.Next, it was ice-cooled again and 2.5 ml of chloromethyl ether wasdropped thereinto. After the completion of the reaction, the reactionmixture was distributed into water and ethyl acetate. The organic layerwas extracted, washed with water and dried over anhydrous sodiumsulfate. After distilling off the solvent under reduced pressure, theresidue was purified by silica gel column chromatography (eluted withethyl acetate/hexane) to thereby give 5.0 g of ethyl10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine-7-carboxylateas pale yellow crystals.

200 ml of a solution of 9.8 g of ethyl10-(methoxymethyl)-10H-pyrazinol2,3-b][1,4]benzothiazine-7-carboxylatein dichloromethane was ice-cooled in a nitrogen atmosphere and 81 ml ofdiisobutylaluminum hydride (1.01 M toluene solution) was droppedthereinto. After the completion of the reaction, ice and celite wereadded to the reaction mixture and stirred at room temperature for 1hour. Then the mixture was diluted with ethyl acetate and filteredthrough celite to thereby separate the organic layer. After distillingoff the solvent under reduced pressure, 8.0 g of the title compound wasobtained as pale yellow crystals.

¹H-NMR(CDCl₃) δ ppm: 1.78(t, J=6.0 Hz, 1H), 3.52(s, 3H), 4.57(d, J=6.0Hz, 2H), 5.25(s, 2H), 7.03(s, 1H), 7.10(d, J=8.2 Hz, 1H), 7.12(d, J=8.2Hz, 1H), 7.82(d, J=2.8 Hz, 1H), 7.83(d, J=2.8 Hz, 1H)

Examples 159 and 160

Starting with methyl10H-pyrimido[5,4-b][1,4]-benzothiazine-8-carboxylate and methyl5-(methoxymethyl)-5H-pyrido[3,4-b][1,4]benzothiazine-7-carboxylate, thefollowing compounds were obtained by the same procedure as the one ofExample 6.

Ex. Structural formula NMR 159

¹H-NMR (DMSO-d₆) δ ppm: 4.30(d, J=6.5Hz, 2H), 5.17(t, J=6.5Hz, 1H),6.76(d, J=7.4Hz, 1H), 6.80(s, 1H), 6.87(d, J=7.4Hz, 1H), 7.84-8.00(br.s, 1H), 8.22(s, 1H), 9.83(s, 1H) 160

¹H-NMR (CDCl₃) δ ppm: 3.54(s, 3H), 4.65(s, 2H), 5.03(s, 2H), 6.87(d,J=6Hz, 1H), 7.00(d, J=8Hz, 1H), 7.08(s, 1H), 7.09(d, J=8Hz, 1H), 8.18(s,1H), 8.27(d, J=6Hz, 1H)

Example 1614-Cyano-10-(methoxymethyl)-10H-pyrido[3,2-b][1,4]-benzothiazine-8-methanol

To a solution of 0.19 g of methyl4-cyano-10-(methoxymethyl)-10H-pyrido[3,2-b][1,4]-benzothiazine-8-carboxylatein dry tetrahydrofuran (5 ml) was added in a nitrogen atmosphere asolution of 0.026 g of lithium borohydride in tetrahydrofuran (10 ml)and the resulting mixture was heated under reflux for 20 minutes. Afterbringing back to room temperature, the mixture was extracted with 15 mlof water and 15 ml of acetic acid and dried over anhydrous magnesiumsulfate. After distilling off the solvent under reduced pressure, theresidue was purified by silica gel column chromatography (eluted withdichloromethane/methanol) to thereby give 0.12 g of the title compoundas a pale yellow solid.

¹H-NMR(CDCl₃) δ ppm: 1.92(br.s, 1H), 3.39(s, 3H), 4.68(s, 2H), 5.34(s,2H), 7.09(dd, J=2, 8 Hz, 1H), 7.14(d, J=8 Hz, 1H), 7.18(d, J=2 Hz, 1H),7.22(d, J=5 Hz, 1H), 8.16(d, J=5 Hz, 1H)

Examples 162 to 165

The following compounds were obtained by the same procedure as the oneof Example 3.

Ex. Structural formula NMR 162

¹H-NMR (CDCl₃) δ ppm: 1.74(br.s, 1H), 3.46(s, 3H), 4.58(s, 2H), 5.31(s,2H), 6.82-6.86(m, 2H), 6.92-6.94(m, 1H), 7.43(d, J=3Hz, 1H), 7.78(d,J=3Hz, 1H) 163

¹H-NMR (DMSO-d₆) δ ppm: 4.28(d, J=6Hz, 2H), 5.12(t, J=6Hz, 1H), 6.60(d,J=8Hz, 1H), 6.61(s, 1H), 6.69(d, J=8Hz, 1H), 7.24(d, J=3Hz, 1H), 7.44(d,J=3Hz, 1H), 9.63(s, 1H) 164

¹H-NMR (CDCl₃) δ ppm: 4.56(s, 2H), 6.58- 6.60(m, 1H), 6.64- 6.70(m, 1H),6.71(dd, J=5, 7Hz, 1H), 6.80- 6.84(m, 1H), 6.98(m, 1H), 7.17(dd, J=1,7Hz, 1H), 7.81(dd, J=1, 5Hz, 1H) 165

¹H-NMR (CDCl₃) δ ppm: 2.23(t, J=6Hz, 1H), 3.52(s, 3H), 3.82(s, 3H),4.62(d, J=6Hz, 2H), 5.26(s, 2H), 6.54(s, 1H), 7.13(s, 1H), 7.82(s, 2H)

Examples 166 to 171

The following compounds were obtained by the same procedure as the oneof Example 4.

Ex. Structural formula NMR 166

¹H-NMR (CDCl₃) δ ppm: 3.25(s, 3H), 4.48(s, 2H), 5.3(s, 2H), 6.81(d,J=8Hz, 1H), 6.88(d, J=8Hz, 1H), 6.93(s, 1H), 7.43(s, 1H), 7.58(s, 1H)167

¹H-NMR (DMSO-d₆) δ ppm: 4.58(s, 2H), 6.65(s, 1H), 6.75(s, 2H), 7.26(s,1H), 7.46(s, 1H), 9.73(s, 1H) 168

¹H-NMR (CDCl₃) δ ppm: 4.41(s, 2H), 6.70(dd, J=2, 8Hz, 1H), 6.76(d,J=2Hz, 1H), 6.85(d, J=8Hz, 1H), 6.91(dd, J=2, 8Hz, 1H), 7.22(dd, J=2,7Hz, 1H), 7.56(dd, J=1, 6Hz, 1H), 9.3-9.4(m, 1H) 169

¹H-NMR (CDCl₃) δ ppm: 3.60(s, 3H), 4.55(s, 2H), 5.09(s, 2H),7.09-7.13(m, 3H), 7.18(dd, J=2, 8Hz, 1H), 8.21(s, 1H), 8.33(d, J=6Hz,1H) 170

¹H-NMR (CDCl₃) δ ppm: 3.40(s, 3H), 4.65(s, 2H), 5.33(s, 2H), 7.12(dd,J=2, 8Hz, 1H), 7.15(d, J=8Hz, 1H), 7.18(d, J=2Hz, 1H), 7.25(d, J=5Hz,1H), 8.18(d, J=5Hz, 1H) 171

¹H-NMR (CDCl₃) δ ppm: 3.51(s, 3H), 4.47(s, 2H), 5.26(s, 2H), 7.04(d,J=1.8Hz, 1H), 7.12(d, J=7.9Hz, 1H), 7.14(dd, J=1.8, 7.9Hz, 1H), 7.83(d,J=2.7Hz, 1H), 7.85(d, J=2.7Hz, 1H)

Example 1728-(Chloromethyl)-10-(methoxymethyl)-10H-pyrazino[2,3-b]pyrido[3,2-e][1,4]thiazine

Methyl10-(methoxymethyl)-10H-pyrazino[2,3-b]pyrido[3,2-e][1,4]thiazine-8-carboxylatewas treated in the same manner as those of Examples 6 and 4 to therebygive the title compound as yellow crystals.

¹H-NMR(CDCl₃) δ ppm: 3.52(s, 3H), 4.49(s, 2H), 5.26(s, 2H), 7.32(d,J=2.0 Hz, 1H), 7.81(d, J=2.6 Hz, 1H), 7.86(d, J=2.6 Hz, 1H), 8.02(d,J=2.0 Hz, 1H)

Example 1737-Methoxy-10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]-benzoxazine-8-carboxaldehyde

To a solution of 1.17 g of7-methoxy-10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]-benzoxazine-8-methanolin 50 ml of 1,2-dichloroethane was added 3.2 g of manganese dioxide andthe resulting mixture was heated under reflux for 2 hours. The reactionmixture was filtered through celite. After distilling off the solventunder reduced pressure, 0.75 g of the title compound was obtained as abrown solid.

¹H-NMR(CDCl₃) δ ppm: 3.53(s, 3H), 3.89(s, 3H), 5.26,(s, 2H), 6.66(s,1H), 7.53(s, 1H), 7.84(d, J=3 Hz, 1H), 7.87(d, J=3 Hz, 1H)10.34(s, 1H)

Example 17410-(Methoxymethyl)-10H-pyrazino[2,3-b][1,4]-benzothiazine-8-carboxaldehyde

To a solution of 20 g of10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]-benzoxazine-8-methanol in200 ml of dichloromethane was added 132 g of manganese dioxide and theresulting mixture was reacted at room temperature for 18 hours. Afterfiltering off the manganese dioxide, the filtrate was concentrated tothereby give 16 g of the title compound as yellow crystals.

¹H-NMR(CDCl₃) δ ppm: 3.56(s, 3H), 5.32(s, 2H), 7.15(d, J=8.0 Hz, 1H),7.45(dd, J=1.6, 8.0 Hz, 1H), 7.58(d, J=1.6 Hz, 1H), 7.87(s, 2H), 9.90(s,1H)

Example 175 Ethyl3-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]-benzothiazin-8-yl]propanoate

1.5 g of10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]-benzothiazine-8-carboxaldehydewas successively treated in the same manners as those of ProductionExample 25 and Example 20 to thereby give 1.3 g of the title compound asa yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.15-1.20(m, 3H), 2.53(t, J=8 Hz, 2H), 2.83(t, J=8Hz, 2H), 3.46(s, 3H), 4.0-4.1(m, 2H), 5.20(s, 2H), 6.75(d, J=8 Hz, 1H),6.86(d, J=8 Hz, 1H), 6.94(s, 1H), 7.95(s, 2H)

Example 1763-[10-(Methoxymethyl)-10H-pyrazino[2,3-b][1,4]-benzothiazin-8-yl]propionaldehyde

1.3 g of ethyl3-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]-benzothiazin-8-yl]propanoatewas successively treated in the same manners as those of ProductionExample 64 and Example 7 to thereby give 0.5 g of the title compound asa yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 2.79(t, J=8 Hz, 2H), 2.90(t, J=8 Hz, 2H), 3.54(s,3H), 5.27(s, 2H), 6.80(d, J=8 Hz, 1H), 6.94(d, J=8 Hz, 1H), 7.00(s, 1H),7.9-7.95(m, 2H), 9.83(s, 1H)

Example 1773-(10-(Methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)propylmethanesulfonate

3.0 g of ethyl3-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)propanoatewas treated successively by the methods described in Example 3 andProduction Example 52 to thereby give 2.7 g of the title compound as ayellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 2.06(quint., J=7.2 Hz, 2H), 2.70(t, J=7.2 Hz, 2H),2.88(s, 3H), 3.54(s, 3H), 4.23(t, J=7.2 Hz, 2H), 5.27(s, 2H), 6.82(d,J=8.6 Hz, 1H), 6.96(d, J=8.6 Hz, 1H), 6.99(s, 1H), 7.84(s, 2H)

Example 178 10H-Pyrazino[2,3-b][1,4]benzothiazine-8-ethanol

Starting with 2.3 g of methyl10H-pyrazino[2,3-b][1,4]benzothiazine-8-acetate, the procedure ofExample 3 was repeated to thereby give 2.5 g of the. title compound as abrown oily substance.

¹H-NMR(CDCl₃) δ ppm: 2.51(t, J=7 Hz, 2H), 3.33(br.s, 1H), 3.50(t, J=7Hz, 2H), 6.62(s, 1H), 6.63(d, J=8 Hz, 1H), 6.78(d, J=8 Hz, 1H),7.58-7.65(m, 2H), 9.44(m, 1H)

Example 1798-[(2-(tert-Butyldimethylsiloxy)ethyl]-10H-pyrazin[2,3-b][1,4]benzothiazine

500 mg of 2-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)ethanol wasdissolved in 7 ml of N,N-dimethylformamide. After adding 369 mg oftert-butyldimethylsilyl chloride, 0.34 ml of triethylamine and acatalytic amount of 4-dimethylaminopyridine, the resulting mixture wasstirred at room temperature for 14 hours. After adding water, thereaction mixture was extracted with ethyl acetate. The ethyl acetatelayer was washed with water and a saturated aqueous solution of sodiumchloride, dried over anhydrous sodium sulfate and concentrated underreduced pressure. Then the residue was purified by silica gel columnchromatography (eluted with n-hexane/ethyl acetate) to thereby give 671mg of the title compound as a yellow solid.

¹H-NMR(CDCl₃) δ ppm: 0.00(s, 6H), 0.87(s, 9H), 2.66(t, J=6.8 Hz, 2H),3.75(t, J=6.8 Hz, 2H), 6.37(d, J=1.6 Hz, 1H), 6.57(br.s, 1H), 6.69(dd,J=1.6, 7.9 Hz, 1H), 6.80(d, J=7.9 Hz, 1H), 7.56(d, J=2.9 Hz, 1H),7.69(d, J=2.9 Hz, 1H)

Example 1808-[(2(tert-Butyldimethylsiloxy)ethyl]-10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine

603 mg of8-[(2-(tert-butyldimethylsilyloxy)ethyl]-10H-pyrazino[2,3-b][1,4]benzothiazinewas dissolved in 6 ml of tetrahydrofuran. After adding 63 mg of 70%sodium hydride, the resulting mixture was stirred under ice-cooling for15 minutes. Then 0.14 ml of chloromethyl methyl ether was added theretoand the resulting mixture was stirred for 1 hour and for additional 18hours at room temperature. The reaction mixture was concentrated underreduced pressure and the residue was purified by silica gel columnchromatography (eluted with n-hexane/ethyl acetate) to thereby give 463mg of the title compound as a brown oily substance.

¹H-NMR(CDCl₃) δ ppm: 0.01(s, 6H), 0.88(s, 9H), 2.76(t, J=7.0 Hz, 2H),3.53(s, 3H), 3.79(t, J=7.0 Hz, 2H), 5.27(s, 2H), 6.83(dd, J=1.6, 7.9 Hz,1H), 6.93(d, J=7.9 Hz, 1H), 7.00(d, J=1.6 Hz, 1H), 7.82(d, J=2.7 Hz,1H), 7.83(d, J=2.7 Hz, 1H)

Example 18110-(Methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine-8-ethanol

463 mg of8-[(2-(tert-butyldimethylsilyloxy)ethyl]-10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazinewas dissolved in 5 ml of tetrahydrofuran. After adding 1.3 ml ofn-tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran), theresulting mixture was stirred at room temperature for 1 hour and then at4° C. for additional 13 hours. The reaction mixture was concentratedunder reduced pressure and the residue was purified by silica gel columnchromatography (eluted with n-hexane/ethyl acetate) to thereby give 281mg of the title compound as a pale orange solid.

¹H-NMR(CDCl₃) δ ppm: 1.51(t, J=5.5 Hz, 1H), 2.82(t, J=6.6 Hz, 2H),3.54(s, 3H), 3.85(dt, J=5.5, 6.6 Hz, 2H), 5.28(s, 2H), 6.86(dd, J=1.6,7.9 Hz, 1H), 6.96(d, J=7.9 Hz, 1H), 7.03(d, J=1.6 Hz, 1H), 7.83(d, J=2.7Hz, 1H), 7.84(d, J=2.7 Hz, 1H)

Example 1828-[2-(Methanesulfonyloxy)ethyl]-10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine

Starting with10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine-8-ethanol, thetitle compound was obtained by the same method as the one of ProductionExample 52.

¹H-NMR(CDCl₃) δ ppm: 2.94(s, 3H), 3.00(t, J=6.8 Hz, 2H), 3.54(s, 3H),4.40(t, J=6.8 Hz, 2H), 5.28(s, 2H), 6.85(dd, J=1.6, 7.9 Hz, 1H), 6.97(d,J=7.9 Hz, 1H), 7.04(d, J=1.6 Hz, 1H), 7.83(d, J=2.7 Hz, 1H), 7.85(d,J=2.7 Hz, 1H)

Example 183 2-Benzyl-7-(methoxymethoxy)-2-azaspiro[3,5]nonane

11.91 g of 4-(methoxymethoxy)cyclohexane-1,1-dimethyl dimethanesulfonatewas dissolved in 30 ml of diphenyl ether. After adding 5.94 g ofanhydrous potassium carbonate and 7.23 ml of benzylamine, the resultingmixture was stirred at 180° C. for 21 hours. Then water was added to thereaction mixture followed by extraction with ethyl acetate. The organiclayer was washed with water and a saturated aqueous solution of sodiumchloride, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluted with dichloromethane/methanol) to thereby give5.15 g of the title compound as a pale yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.32-1.43(m, 2H), 1.44-1.53(m, 2H), 1.74-1.82(m,2H), 1.86-1.96(m, 2H), 3.00(s, 2H), 3.04(s, 2H), 3.36(s, 3H), 3.51(m,1H), 3.65(s, 2H), 4.66(s, 2H), 7.21-7.34(m, 5H)

Example 184 2-Benzyl-2-azaspiro[3,5]nonan-7-one

900 mg of 2-benzyl-7-(methoxymethyloxy)-2-azaspiro-[3,5]nonane wasdissolved in 40 ml of acetone. After adding 10 ml of 6 N hydrochloricacid, the resulting mixture was stirred at room temperature for 1.5hours. Then the reaction mixture was concentrated under reduced pressureand an aqueous solution of potassium hydrogencarbonate was added theretofollowed by extraction with ether. The organic layer was washed withwater and a saturated aqueous solution of sodium chloride, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Thus,794 mg of a pale yellow oily substance was obtained.

0.43 ml of oxalyl chloride was dissolved in 8 ml of dichloromethane andstirred under cooling to −70° C. 0.37 ml of dimethyl sulfoxide wasdissolved in 1 ml of dichloromethane and dropped into the above solutionwhile maintaining the inner temperature at −50° C. or below. 10 minutesthereafter, 794 mg of the oily substrate obtained above was dissolved in2 ml of dichloromethane and dropped into the mixture while maintainingthe bulk temperature at −50° C. or below. 25 minutes thereafter, 2.3 mlof triethylamine was dropped thereinto. After 15 minutes, the mixturewas heated to room temperature and stirred for 1 hour. After addingwater, the reaction mixture was extracted with ethyl acetate. Theorganic layer was washed with water and a saturated aqueous solution ofsodium chloride, dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (eluted with dichloromethane/methanol) to thereby give655 mg of the title compound as a pale yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 2.06(t, J=7.0 Hz, 4H), 2.31(t, J=7.0 Hz, 4H),3.17(s, 4H), 3.69(s, 2H), 7.23-7.35(m, 5H)

Example 185 8-Benzyl-8-azabicyclo[4.3.0]nonan-3-ol

8.33 g of 8-benzyl-8-azabicyclo[4.3.0]-3-nonene was dissolved in 100 mlof tetrahydrofuran and 167 ml of a 1 M solution of borane intetrahydrofuran was dropped thereinto in a nitrogen atmosphere underice-cooling. Then the resulting mixture was brought back to roomtemperature and stirred for 1 hour and 15 minutes. To the reactionmixture were added 50 ml of a 4 N aqueous solution of sodium hydroxideand 23 ml of a 30% aqueous solution of hydrogen peroxide underice-cooling and the resulting mixture was stirred at the sametemperature for 1 hour. The reaction mixture was then concentrated underreduced pressure, extracted with ethyl acetate and concentrated underreduced pressure. 6 N hydrochloric acid was added to the residue and theresulting mixture was stirred at 90° C. for 20 minutes. The reactionmixture was ice-cooled and made basic by adding sodium hydroxidepellets. Then it was extracted with ethyl acetate and the organic layerwas dried over anhydrous potassium carbonate. After filtration, thesolvent was distilled off under reduced pressure to thereby give 8.29 gof the title compound as a pale yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.24-1.91(m, 7H), 2.02-2.36(m, 2H), 2.42-2.89(m,4H), 3.63-3.91(m, 3H), 7.20-7.4(m, 5H)

Example 186 8-(tert-Butoxycarbonyl)-8-azabicyclo[4.3.0]nonan-3-ol

6.87 g of 8-benzyl-8-azabicyclo[4.3.0]nonan-3-ol was dissolved in 100 mlof methanol and 500 mg of palladium-carbon and 4 ml of formic acid wereadded thereto. The resulting mixture was stirred at 50° C. for 20minutes and then at 65° C. for 4 hours and 20 minutes. After furtheradding 500 mg of palladium-carbon and 3 ml of formic acid, the resultingmixture was heated under reflux for 3 hours. After filtering off thepalladium-carbon, the solvent was distilled off under reduced pressure.The residue was then dissolved in 150 ml of methanol. After adding 7 mlof triethylamine and 6.5 g of t-butyl dicarbonate, the resulting mixturewas stirred at room temperature for 20 minutes. The reaction mixture wasconcentrated under reduced pressure, diluted with ethyl acetate, washedsuccessively with 1 N hydrochloric acid, a saturated solution of sodiumhydrogencarbonate and a saturated aqueous solution of sodium chlorideand dried over anhydrous magnesium sulfate. After filtration, thesolvent was concentrated under reduced pressure. The residue thusobtained was purified by silica gel column chromatography (eluted withn-hexane/ethyl acetate) to thereby give 3.73 g of the title compound asa colorless oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.30-1.43(m, 2H), 1.45(s, 9H), 1.50-1.59(m, 1H),1.75-1.90(m, 3H), 2.07-2.21(m, 1H), 2.42-2.52(m, 1H), 3.11-3.22(m, 2H),3.30-3.43(m, 3H), 3.85-3.93(m, 1H)

Example 187 8-(tert-Butoxycarbonyl)-8-azabicyclo[4.3.0]nonan-3-one

4.9 g of oxalyl chloride was dissolved in 250 ml of dichloromethane andcooled to −78° C. in a nitrogen atmosphere. Then a solution of 4.83 g ofdimethyl sulfoxide in dichloromethane (20 ml) was dropped thereinto over17 minutes. Subsequently, a solution of 3.73 g of8-(tert-butoxycarbonyl)-8-azabicyclo[4.3.0]nonan-3-ol in dichloromethane(40 ml) was dropped thereinto over 10 minutes. After stirring for 10minutes, 7.82 g of triethylamine was dropped thereinto over 10 minutesand stirring was continued for additional 1 hour. The reaction mixturewas brought back to room temperature, diluted with dichloromethane,washed with water and a saturated aqueous solution of sodium chlorideand then dried over anhydrous magnesium sulfate. After filtration, thesolvent was distilled off under reduced pressure. The residue thusobtained was purified by silica gel column chromatography (eluted withn-hexane/ethyl acetate) to thereby give 3.21 g of the title compound asa colorless oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.45(s, 9H), 1.81-1.93(m, 1H), 2.00-2.10(m, 1H),2.30-2.55(m, 5H), 2.65-2.75(m, 1H), 3.05-3.14(m, 1H), 3.30-3.38(m, 1H),3.48-3.55(m, 2H)

Examples 188 to 191

Appropriate known compounds were treated in the same manner as thosedescribed in Production Example 14 and Example 16 to thereby give thefollowing compounds.

Ex. Structural Formula NMR 188

¹H-NMR (CDCl₃) δ ppm: 1.46(s, 9H), 1.69(t, J=6Hz, 4H), 2.81(s, 4H),3.41(t, J=6Hz, 4H) 189

¹H-NMR (CDCl₃) δ ppm: 1.45(s, 9H), 1.75(dd, J=6.4, 13.2Hz, 2H), 2.11(dd,J=7.6, 13.2Hz, 2H), 2.67-2.99(m, 2H), 2.88(d, J=2.4Hz, 2H), 3.04(dd,J=3.2, 4.0Hz, 2H), 3.23-3.36(m, 2H), 3.41- 3.52(m, 2H) 190

¹H-NMR (CDCl₃) δ ppm: 1.46(s, 9H), 2.01-2.08(m, 2H), 2.90- 3.14(m, 4H),3.36- 3.53(m, 4H), 191

¹H-NMR (CDCl₃) δ ppm: 1.08-1.21(m, 2H), 1.34- 1.50(m, 1H), 1.46(s, 9H),1.67-1.77(m, 2H), 2.04- 2.17(m, 1H), 2.60- 2.80(m, 2H), 2.72- 2.83(m,2H), 3.03- 3.14(m, 2H), 4.01- 4.27(m, 2H)

Example 192 1-Benzyl-2-methyl-4-piperidone

6.97 g of 4-methoxy-2-methylpyridine was dissolved in 200 ml of acetoneand 13.5 g of benzyl bromide was added thereto. Then the resultingmixture was heated under reflux for 2 hours and 30 minutes. The reactionmixture was cooled to room temperature and diluted with diethyl ether.The precipitate was taken up by filtration and the solid matter wasdissolved in 60 ml of water. Next, 5.35 g of sodium borohydride wasadded thereto in portions. After stirring for 15 minutes, the reactionmixture was concentrated under reduced pressure, diluted with ethylacetate, washed successively with water and a saturated aqueous solutionof sodium chloride and dried over anhydrous magnesium sulfate. Afterfiltration, the solvent was distilled off under reduced pressure. To theobtained residue was added 5 N hydrochloric acid and the resultingmixture was stirred at room temperature overnight. The reaction mixturewas made basic by adding potassium carbonate, extracted with ethylacetate, washed with a saturated aqueous solution of sodium chloride anddried over anhydrous magnesium sulfate. After filtration, the solventwas distilled off under reduced pressure and the residue was purified bysilica gel column chromatography (eluted with n-hexane/ethyl acetate) tothereby give 6.84 g of the title compound as a colorless oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.18(d, J=6.4 Hz, 3H), 2.29(dd, J=7.6, 14.4 Hz,1H), 2.34-2.42(m, 2H), 2.50-2.60(m, 2H), 2.94-3.06(m, 2H), 3.45(d,J=12.8 Hz, 1H), 3.97(d, J=12.8 Hz, 1H), 7.25-7.40(m, 5H)

Example 193 1-Benzyl-2-methyl-4-methylenepiperidine

6.84 g of 1-benzyl-2-methyl-4-piperidone was treated in the same manneras the one of Production Example 14 to thereby give 6.41 g of the titlecompound as a pale yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.14(d, J=6.0 Hz, 3H), 2.00-2.38(m, 5H),2.46-2.62(m, 1H), 2.70-2.82(m, 1H), 3.26-3.38(m, 1H), 3.87-4.00(m, 1H),4.65(d, J=10.4 Hz, 2H), 7.14-7.42(m, 5H)

Example 194 1-(tert-Butoxycarbonyl)-2-methyl-4-methylenepiperidine

6.41 g of 1-benzyl-2-methyl-4-methylenepiperidone was dissolved in 70 mlof dichloroethane and 5.92 g of 1-chloroethyl chloroformate was addedthereto under ice-cooling. After heating the mixture under reflux for 50minutes, 100 ml of methanol was added thereto and the resulting mixturewas allowed to stand at room temperature overnight. Then triethylaminewas added to the reaction mixture under ice-cooling until the pH valuereached 9. Further, 7.64 g of tert-butyl dicarbonate was added theretoand the resulting mixture was stirred at room temperature for 1 hour.The reaction mixture was concentrated under reduced pressure, dilutedwith ethyl acetate, washed successively with water, 1 N hydrochloricacid, a saturated aqueous solution of sodium chloride and a saturatedaqueous solution of sodium bicarbonate and dried over anhydrousmagnesium sulfate. After filtration, the solvent was distilled off underreduced pressure and the obtained residue was purified by silica gelcolumn chromatography (eluted with n-hexane/ethyl acetate) to therebygive 7.2 g of the title compound as a colorless oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.06(d, J=6.8 Hz, 3H), 1.47(s, 9H), 1.99-2.05(m,1H), 2.08-2.23(m, 2H), 2.35-2.43(m, 1H), 2.81-2.90(m, 1H), 3.98-4.06(m,1H), 4.45-4.55(m, 1H), 4.72-4.75(m, 1H), 4.83-4.86(m, 1H)

Example 195 7-(tert-Butoxycarbonyl)-6-methyl-7-azaspiro[3.5]nonan-2-one

7.2 g of 1-(tert-butoxycarbonyl)-2-methyl-4-methylenepiperidine wastreated in the same manner as the one described in Production Example 16to thereby give 2.98 g of the title compound as a yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.10-1.18(m, 3H), 1.47(s, 9H), 1.61-1.75(m, 3H),2.00(dd, J=6.4, 13.6 Hz, 1H), 2.72-3.04(m, 5H), 4.01-4.09(m, 1H),4.42-4.52(m, 1H)

Example 196 1-Benzyl-4-[4-[2-(methoxymethoxy)ethyl]phenyl]piperidin-4-ol

Into a solution of 10 g of 4-bromophenethyl methoxymethyl ether in 200ml of tetrahydrofuran was dropped 28 ml of a 1.6 M solution ofn-butyllithium in hexane at −78° C. and the resulting mixture wasstirred at the same temperature for 30 minutes. After heating to −20°C., a solution of 7.0 g of 1-benzyl-4-piperidone in tetrahydrofuran (10ml) was added thereto. The mixture was reacted at the same temperaturefor 2 hours. After adding water, the resulting mixture was extractedwith ethyl acetate, washed with a saturated aqueous solution of sodiumchloride and dried over anhydrous magnesium sulfate. After distillingoff the solvent under reduced pressure, 7.6 g of the title compound wasobtained as a yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.65(br.t, J=13 Hz, 2H), 2.0-2.18(m, 2H),2.40(br.t, J=10 Hz, 2H), 2.6-2.75(m, 2H), 2.83(t, J=7 Hz, 2H), 3.23(s,3H), 3.51(s, 2H), 3.69(t, J=7 Hz, 2H), 4,54(s, 2H), 7.1-7.35(m, 7H),7.35(d, J=8 Hz, 2H)

Example 197 4-(1-Benzyl-1,2,5,6-tetrahydropyrid-4-yl)phenethyl alcohol

To a solution of 1.0 g of1-benzyl-4-[4-[2-(methoxymethoxy)ethyl]phenyl]piperidin-4-ol in 30 ml oftoluene was added 2.0 g of p-toluenesulfonic acid. Then the resultingmixture was heated under reflux for 1 hour while eliminating the waterthus formed with a Dean Stark trap. Then the reaction mixture wasbrought back to room temperature and a saturated aqueous solution ofsodium bicarbonate was added thereto. Then it was extracted with ethylacetate, washed with a saturated aqueous solution of sodium chloride anddried over anhydrous magnesium sulfate. After distilling off the solventunder reduced pressure, the residue was purified by silica gel columnchromatography (eluted with n-hexane/ethyl acetate) to thereby give 0.2g of the title compound as a brown oily substance.

¹H-NMR(CDCl₃) δ ppm: 2.55(m, 2H), 2.71(t, J=6 Hz, 2H), 2.85(t, J=6 Hz,2H), 3.17(dd, J=2, 6 Hz, 2H), 3.64(s, 2H), 3.84(t, J=6 Hz, 2H), 6.04(m,1H), 7.14-7.40(m, 9H)

Examples 198 to 202

The following compounds were obtained by the same methods as thosedescribed in Examples 196 and 197.

Ex. Structural formula NMR 198

¹H-NMR (CDCl₃) δ ppm: 2.43(br.s, 2H), 2.55-2.65(m, 2H), 3.03(br.s, 2H),3.55(s, 2H), 6.18(s, 1H), 7.2- 7.5(m, 9H) 199

¹H-NMR (CDCl₃) δ ppm: 2.5-2.57(m, 2H), 2.70(t, J=6Hz, 2H), 3.15(d,J=3Hz, 2H), 3.63(s, 2H), 5.05(s, 2H), 5.97(s, 1H), 6.92(d, J=9Hz, 2H),7.23- 7.45(m, 12H) 200

¹H-NMR (CDCl₃) δ ppm: 2.54(s, 2H), 2.71(t, J=5Hz, 2H), 2.93(t, J=5Hz,2H), 3.16(s, 2H), 3.65(s, 2H), 3.69(t, J=5Hz, 2H), 4.52(s, 2H), 6.04(s,1H), 7.10(s, 1H), 7.2-7.4(m, 13H) 201

¹H-NMR (CDCl₃) δ ppm: 2.53(s, 2H), 2.70(t, J=6Hz, 2H), 2.95(t, J=6Hz,2H), 3.15(s, 2H), 3.63(s, 2H), 3.6- 3.7(m, 2H), 3.78(s, 3H), 4.53(s,2H), 5.94(s, 1H), 7.2-7.4(m, 13H) 202

¹H-NMR (CDCl₃) δ ppm: 2.52(br.s, 2H), 2.70(t, J=6Hz, 2H), 2.95(t, J=8Hz,2H), 3.16(dd, J=3, 6Hz, 2H), 3.64(s, 2H), 3.66(t, J=8Hz, 2H), 3.79(s,3H), 3.85(s, 3H), 4.52(s, 2H), 5.94-5.98(m, 1H), 6.81(d, J=2Hz, 1H),6.84(d, J=2Hz, 1H), 7.22-7.40(m, 10H)

Example 203 4-[1-(Benzyloxycarbonyl)piperidin-4-yl]phenethyl alcohol

To a solution of 8.0 g of4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)phenethyl alcohol in ethanol(200 ml) was added 15 g of 10% palladium-carbon (moisture content: 50%)and hydrogenation was effected at ordinary temperature under atmosphericpressure for 12 hours. After the completion of the reaction, thepalladium-carbon was filtered off and the filtrate was distilled underreduced pressure to thereby give 4.0 g of crude4-(piperidin-4-yl)phenethyl alcohol as a colorless oily substance. To4.0 g of this crude product and 3.3 ml of triethylamine dissolved indichloromethane (30 ml) was added 3.1 ml of benzyl chloroformate at 0°C. and the mixture was reacted at room temperature for 1 hour. Afteradding water, the reaction mixture was extracted with ethyl acetate,washed with a saturated aqueous solution of sodium chloride and driedover anhydrous magnesium sulfate. After distilling off the solvent underreduced pressure, the residue was purified by silica gel columnchromatography (eluted with n-hexane/ethyl acetate) to thereby give 4.0g of the title compound as a yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.55-1.70(m, 2H), 1.77-1.90(m, 2H), 2.6-2.7(m, 1H),2.84(t, J=7 Hz, 2H), 2.8-3.0(m, 2H), 3.8-3.9(m, 2H), 4.2-4.4(m, 2H),5.15(s, 2H), 7.14(d, J=8 Hz, 2H), 7.18(d, J=8 Hz, 2H), 7.30-7.40(m, 5H)

Examples 204 and 205

The following compounds were obtained by the same method as that ofExample 203.

Ex. Structural formula NMR 204

¹H-NMR (CDCl₃) δ ppm: 1.50-1.70(m, 2H), 1.77- 1.85(m, 2H), 2.55- 2.65(m,1H), 2.8-3.0(m, 2H), 4.2-4.4(m, 2H), 5.15(s, 2H), 6.78(d, J=7Hz, 2H),7.04(d, J=7Hz, 2H), 7.3-7.4(m, 5H) 205

¹H-NMR (CDCl₃) δ ppm: 1.55-1.73(m, 2H), 1.8- 1.9(m, 2H), 2.6-2.7(m, 1H),2.85(t, J=6Hz, 2H), 2.8-3.0(m, 2H), 3.86(t, J=6Hz, 2H), 4.2-4.4(m, 2H),5.16(s, 2H), 7.04-7.12(m, 3H), 7.23- 7.41(m, 6H)

Example 206 2-[1-(Benzyloxycarbonyl)piperidin-4-yl]phenethyl alcohol

The title compound was obtained by the same operations as thosedescribed in Examples 196, 197 and 203.

¹H-NMR(CDCl₃) δ ppm: 1.5-1.8(m, 4H), 2.8-3.0(m, 2H), 2.95(t, J=7 Hz,2H), 3.83(t, J=7 Hz, 2H), 4.11(q, J=7 Hz, 2H), 4.2-4.4(m, 2H), 5.15(s,2H), 7.1-7.3(m, 4H), 7.3-7.4(m, 5H)

Example 207 4-[1-(Benzyloxycarbonyl)piperidin-4-yl]phenylacetaldehyde

4.0 g of 4-[1-(benzyloxycarbonyl)piperidin-4-yl]phenethyl alcohol wastreated in the same manner as the one of Production Example 7 to therebygive 1.7 g of the title compound as a yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.55-1.70(m, 2H), 1.77-1.90(m, 2H), 2.6-2.73(m,1H), 2.7-3.0(m, 2H), 3.67(d, J=1 Hz, 2H), 4.2-4.43(m, 2H), 5.16(s, 2H),7.16(d, J=8 Hz, 2H), 7.20(d, J=8 Hz, 2H), 7.3-7.4(m, 5H), 9.74(t, J=2Hz, 1H)

Examples 208 to 210

The following compounds were obtained by the same procedure as the oneof Production Example 7.

Ex. Structural formula NMR 208

¹H-NMR (CDCl₃) δ ppm: 1.5-1.75(m, 2H), 1.75- 1.9(m, 2H), 2.6-2.75(m,1H), 2.8-3.0(m, 2H), 3.67(d, J=2Hz, 2H), 4.3-4.45(m, 2H), 5.16(s, 2H),7.0-7.4(m, 9H), 9.74(t, J=2Hz, 1H) 209

¹H-NMR (CDCl₃) δ ppm: 1.57-1.8(m, 4H), 2.65- 2.8(m, 1H), 2.75- 3.0(m,2H), 3.77(s, 2H), 4.2-4.45(m, 2H), 5.16(s, 2H), 7.1-7.4(m, 9H), 9.75(s,1H) 210

¹H-NMR (CDCl₃) δ ppm: 1.5-1.7(m, 2H), 1.7-1.9(m, 2H), 2.8-3.0(m, 2H),3.0-3.2(m, 1H), 3.60(s, 2H), 3.83(s, 3H),4.2-4.4(m, 2H), 5.15(s, 2H),6.85(d, J=8Hz, 1H), 6.95(s, 1H), 7.04(d, J=8Hz, 1H), 7.2-7.4(m, 5H),9.7(s, 1H)

Example 211 4-[1-(Benzyloxycarbonyl)piperidin-4-yl]phenylacetic acid

To a solution of 0.7 g of4-[1-(benzyloxycarbonyl)-piperidin-4-yl]phenylacetaldehyde and 0.5 g ofsodium dihydrogenphosphate in 5 ml of water and 30 ml of dimethylsulfoxide was added a solution of 0.35 g of sodium chlorite in water (5ml) and the resulting mixture was reacted at room temperature for 20minutes. After adding water, the reaction mixture was extracted withethyl acetate, washed with a saturated aqueous solution of sodiumchloride and dried over anhydrous magnesium sulfate. After distillingoff the solvent under reduced pressure, 0.7 g of the title compound wasobtained as a colorless oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.5-1.7(m, 2H), 1.7-1.9(m, 2H), 2.6-2.7(m, 1H),2.8-3.0(m, 2H), 3.62(s, 2H), 4.2-4.45(m, 2H), 5.15(s, 2H), 7.15(d, J=8Hz, 2H), 7.23(d, J=8 Hz, 2H), 7.28-7.40(m, 5H)

Example 212 Methyl 4-[1-(benzyloxycarbonyl)piperidin-4-yl]phenylacetate

To a solution of 1.55 g of4-[1-(benzyloxycarbonyl)-piperidin-4-yl]phenylacetic acid in methanol(20 ml) was added 13.2 ml of trimethylsilyldiazomethane (2 M solution inhexane) and the resulting mixture was reacted at room temperature for 1hour. After distilling off the reaction mixture under reduced pressure,the residue was purified by silica gel column chromatography (elutedwith n-hexane/ethyl acetate) to thereby give 1.0 of the title compoundas a colorless oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.5-1.7(m, 2H), 1.75-1.88(m, 2H), 2.6-2.7(m, 1H),2.8-2.95(m, 2H), 3.60(s, 2H), 3.69(s, 3H), 4.2-4.4(m, 2H), 5.15(s, 2H),7.15(d, J=8 Hz, 2H), 7.22(d, J=8 Hz, 2H), 7.3-7.4(m, 5H)

Example 213 Methyl 3-[1-(benzyloxycarbonyl)piperidin-4-yl]phenylacetate

To a solution of 2.0 g of3-[1-(benzyloxycarbonyl)-piperidin-4-yl]phenylacetaldehyde and 1.0 g ofsodium dihydrogenphosphate in 10 ml of water and 50 ml of dimethylsulfoxide was added a solution of 2.0 g of sodium chlorite in water (10ml) and the resulting mixture was reacted at room temperature for 20minutes. After adding water, the reaction mixture was extracted withethyl acetate, washed with a saturated aqueous solution of sodiumchloride and dried over anhydrous magnesium sulfate. After distillingoff the solvent under reduced pressure, 2.0 g of crude3-[1-(benzyloxycarbonyl)piperidin-4-yl]phenylacetic acid was obtained asa colorless oily substance. To a solution of 2.0 g of this oilysubstance in 50 ml of methanol was added 0.47 ml of thionyl chloride at0° C. and the resulting mixture was reacted at room temperature for 2hours. The reaction mixture was distilled off under reduced pressure andthe residue was purified by silica gel column chromatography (elutedwith n-hexane/ethyl acetate) to thereby give 1.2 g of the title compoundas a yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.5-1.7(m, 2H), 1.8-1.9(m, 2H), 2.6-2.7(m, 1H),2.8-2.95(m, 2H), 3.61(s, 2H), 3.69(s, 3H), 4.25-4.40(m, 2H), 5.16(s,2H), 7.13-7.16(m, 3H), 7.24-7.40(m, 6H)

Examples 214 to 216

The following compounds were obtained by the same procedure as that ofExample 213.

Ex. Structural formula NMR 214

¹H-NMR (CDCl₃) δ ppm: 1.55-1.8(m, 4H), 2.8-2.95(m, 3H), 3.68(s, 3H),3.70(s, 2H), 4.2- 4.4(m, 2H), 5.16(s, 2H), 7.14-7.40(m, 9H) 215

¹H-NMR (CDCl₃) δ ppm: 1.5-1.7(m, 2H), 1.75-1.85(m, 2H), 2.8- 3.0(m, 2H),3.0-3.2(m, 1H), 3.55(s, 2H), 3.69(s, 3H), 3.81(s, 3H), 4.2- 4.4(m, 2H),5.16(s, 2H), 6.81(d, J=8Hz, 1H), 7.03(d, J=2Hz, 1H), 7.10(dd, J=2, 8Hz,1H), 7.3-7.4(m, 5H) 215

¹H-NMR (CDCl₃) δ ppm: 1.5-1.7(m, 2H), 1.8- 1.9(m, 2H), 2.55- 2.65(m,1H), 2.75- 2.95(m, 2H), 3.63(s, 2H), 3.70(s, 3H), 3.80(s, 3H), 3.95(s,3H), 4.2-4.4(m, 2H), 5.15(s, 2H), 6.64(s, 1H), 6.66(s, 1H), 7.3- 7.40(m,5H)

Example 217 Ethyl 4-[1-benzyl-1,2,3,6-tetrahydropyrid-4-yl]benzoate

To a solution of 11 g of4-(4-bromophenyl)-1-benzyl-1,2,3,6-tetrahydropyridine in 200 ml oftetrahydrofuran was added 27 ml of a 2.5 M solution of n-butyllithium inhexane at −78° C. and the resulting mixture was stirred at the sametemperature for 15 minutes. Into the reaction mixture was dropped 42 mlof diethyl carbonate and the mixture was heated to room temperature over15 minutes. After adding water, the reaction mixture was extracted withethyl acetate, washed with a saturated aqueous solution of sodiumchloride and dried over anhydrous magnesium sulfate. After distillingoff the solvent under reduced pressure, the residue was purified bysilica gel column chromatography (eluted with n-hexane/ethyl acetate) tothereby give 2.8 g of the title compound as a yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.39(t, J=7 Hz, 3H), 2.5-2.62(m, 2H), 2.73(t, J=6Hz, 2H), 3.07-3.11(m, 2H), 3.65(s, 2H), 4.37(q, J=7 Hz, 2H), 6.20(s,1H), 7.24-7.42(m, 5H), 7.44(d, J=8 Hz, 2H), 7.98(d, J=8 Hz, 2H)

Example 218 Ethyl 4-[1-(benzyloxycarbonyl)piperidin-4-yl]phenoxyacetate

To a solution of 0.5 g of [1-(benzyloxycarbonyl)piperidin-4-yl]phenol in20 ml of N,N-dimethylformamide was added 0.083 g of sodium hydride (60%or more oily) and the resulting mixture was stirred at room temperaturefor 10 minutes. Next, ethyl iodoacetate was added thereto and theresulting mixture was reacted at 60° C. for 1.5 hours. The reactionmixture was poured into water, extracted with ethyl acetate, washed witha saturated aqueous solution of sodium chloride and dried over anhydrousmagnesium sulfate. After distilling off the solvent under reducedpressure, the residue was purified by silica gel column chromatography(eluted with n-hexane/ethyl acetate) to thereby give 0.4 g of the titlecompound as a colorless oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.30(t, J=7 Hz, 3H), 1.5-1.70(m, 2H), 1.75-1.90(m,2H), 2.55-2.70(m, 1H), 2.8-2.95(m, 2H), 4.27(q, J=7 Hz, 2H), 4.2-4.4(m,2H), 4.60(s, 2H), 5.15(s, 2H), 6.85(d, J=9 Hz, 2H), 7.11(d, J=9 Hz, 2H),7.28-7.40(m, 5H)

Example 219 Ethyl 4-(1-benzylpiperidin-4-yl)-2-methylpropanoate

To a solution of 40 g of ethyl4-(1-benzylpiperidin-4-yl)-2-methylpropanoate in ethanol (500 ml) wereadded 25 ml of formic acid and 15 g of 10% palladium-carbon (moisturecontent: 50%) and hydrogenation was effected at ordinary temperatureunder atmospheric pressure for 12 hours. Then the palladium-carbon wasfiltered off and the solvent was distilled off. The residue was pouredinto an aqueous solution of sodium bicarbonate and extracted with ethylacetate. The extract was washed with a saturated aqueous solution ofsodium chloride and dried over anhydrous magnesium sulfate. Afterdistilling off the solvent under reduced pressure, 37.8 g of the titlecompound was obtained as a colorless oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.10(t, J=7 Hz, 3H), 1.00-1.25(m, 6H), 1.50-1.80(m,4H), 1.80-1.97(m, 2H), 2.43-2.62(m, 1H), 2.80-2.90(m, 2H), 3.46(s, 2H),4.05-4.18(m, 2H), 7.20-7.30(m, 5H)

Example 220 Ethyl 3-(1-benzylpiperidin-4-yl)-2,2-dimethylpropanoate

To a solution of 68 ml of diisopropylamine in tetrahydrofuran (500 ml)was added 325 ml of a 1.6 M solution of n-butyllithium in hexane and theresulting mixture was stirred at 0° C. for 30 minutes. Then the reactionmixture was cooled to −78° C. and reacted with a solution of 30 g ofethyl 4-(1-benzylpiperidin-4-yl)-2-methylpropanoate in tetrahydrofuran(50 ml) at 0° C. for 30 minutes. After cooling to −78° C. again, 45.3 mlof methyl iodide was dropped thereinto and the resulting mixture wasbrought back to room temperature over 30 minutes. The reaction mixturewas poured into water, extracted with dichloromethane and dried overanhydrous magnesium sulfate. After distilling off the solvent underreduced pressure, the residue was purified by silica gel columnchromatography (eluted with n-hexane/ethyl acetate) to thereby give 21.5g of the title compound as a yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.15(s, 6H), 1.23(t, J=7 Hz, 3H), 1.1-1.4(m, 3H),1.53(d, J=7 Hz, 2H), 1.5-1.60(m, 2H), 1.90(br.t, J=10 Hz, 2H),2.80(br.d, J=10 Hz, 2H), 3.45(s, 2H), 4.08(q, J=7 Hz, 2H), 7.2-7.34(m,5H)

Example 221 Ethyl 2-(1-benzylpiperidin-4-yl)-2-methylpropanoate

Ethyl 2-(1-benzylpiperidin-4-yl)propanoate was treated in the samemanner as the one of Example 27 to thereby give the title compound as anoily substance.

¹H-NMR(CDCl₃) δ ppm: 1.10(s, 6H), 1.23(t, J=7 Hz, 3H), 1.39(dt, J=4, 12Hz, 2H), 1.44-1.52(m, 2H), 1.52-1.62(m, 1H), 1.92(dt, J=2, 12 Hz, 2H),2.93(br.d, J=12 Hz, 2H), 3.48(s, 2H), 4.11(q, J=7 Hz, 2H), 7.2-7.35(m,5H)

Example 2223-[1-(tert-Butoxycarbonyl)piperidin-4-yl]-2,2-dimethylpropanol

Into a solution of 2.7 g of lithium aluminum hydride in tetrahydrofuran(200 ml) was slowly dropped at 0° C. a solution of 21.5 g of ethyl3-(1-benzylpiperidin-4-yl)-2,2-dimethylpropanoate in tetrahydrofuran (20ml) and the resulting mixture was stirred at room temperature for 30minutes. After adding water and a 10% aqueous solution of sodiumhydroxide to the reaction mixture, the insoluble matters were filteredoff. After distilling off the solvent under reduced pressure, 19 g ofcrude 3-(1-benzylpiperidin-4-yl)-2,2-dimethylpropanol was obtained as ayellow oily substance. This oily substance was dissolved in 300 ml ofethanol. After adding 20 ml of acetic acid, the mixture was subjected tohydrogenation at ordinary temperature under atmospheric pressure for 12hours. After filtering off palladium-carbon, the solvent wasconcentrated under reduced pressure to thereby give 23 g of crude3-(piperidin-4-yl)-2,2-dimethylpropanol as a yellow oily substance. Thiscrude product was further dissolved in 200 ml of dichloromethane and 23ml of pyridine was added thereto. Then 15.5 g of di-tert-butyldicarbonate was dropped thereinto at 0° C. and the resulting mixture wasreacted at room temperature for 2 hours. After adding water, thereaction mixture was extracted with ethyl acetate, washed with asaturated aqueous solution of sodium chloride and dried over anhydrousmagnesium sulfate. After distilling off the solvent under reducedpressure, the residue was purified by silica gel column chromatography(eluted with n-hexane/ethyl acetate) to thereby give 14.9 g of the titlecompound as colorless crystals.

¹H-NMR(CDCl₃) δ ppm: 0.9(s, 6H), 1.1-1.2(m, 2H), 1.2(d, J=5 Hz, 2H),1.3-1.4(m, 1H), 1.45(s, 9H), 1.6-1.7(m, 2H), 2.6-2.8(m, 2H), 3.31(s,2H), 3.9-4.1(m, 2H)

Example 2234-[1-(tert-Butoxycarbonyl)piperidin-4-yl]-3,3-dimethyl-butyronitrile

To a solution of 14.9 g of3-[1-(tert-butoxycarbonyl)-piperidin-4-yl]-2,2-dimethylpropanol in 100ml of carbon tetrachloride was added 64 g of triphenylphosphine and theresulting mixture was heated under reflux for 8 hours. The reactionmixture was concentrated under reduced pressure and the residue waspurified by silica gel column chromatography (eluted with n-hexane/ethylacetate) to thereby give 14.7 g of colorless crystals. These crystalswere dissolved in 200 ml of dimethyl sulfoxide and 9.2 g of sodiumiodide and 8.8 g of sodium cyanide were added thereto. After stirring at180° C. for 6 hours, water was added to the mixture at room temperature.Then the reaction mixture was extracted with ethyl acetate, washed witha saturated aqueous solution of sodium chloride and dried over anhydrousmagnesium sulfate. After distilling off the solvent under reducedpressure, the residue was purified by silica gel column chromatography(eluted with n-hexane/ethyl acetate) to thereby give 6.7 g of the titlecompound as a colorless oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.09(s, 6H), 1.1-1.3(m, 2H), 1.33(d, J=5 Hz, 2H),1.45(s, 9H), 1.45(m, 1H), 1.6-1.7(m, 2H), 2.24(s, 2H), 2.6-2.8(m, 2H),3.9-4.1(m, 2H)

Example 224 4-(1-Benzylpiperidin-4-yl)-3,3-dimethylbutyronitrile

To a solution of 6.7 g of4-[1-(tert-butoxycarbonyl)-piperidin-4-yl]-3,3-dimethylbutyronitrile in50 ml of tetrahydrofuran was added at room temperature 20 ml of conc.hydrochloric acid and the resulting mixture was stirred for 2 hours.Then the reaction mixture was concentrated under reduced pressure tothereby give crude 4-(piperidin-4-yl)-3,3-dimethylbutyronitrilehydrochloride. This crude product was dissolved in 100 ml ofdichloromethane. After adding 10.5 g of anhydrous potassium carbonateand 3.3 ml of benzyl bromide, the reaction mixture was reacted at roomtemperature for 12 hours. After adding water, the reaction mixture wasextracted with ethyl acetate, washed with a saturated aqueous solutionof sodium chloride and dried over anhydrous magnesium sulfate. Afterdistilling off the solvent under reduced pressure, the residue waspurified by silica gel column chromatography (eluted with n-hexane/ethylacetate) to thereby give 4.7 g of the title compound as a colorless oilysubstance.

¹H-NMR(CDCl₃) δ ppm: 1.07(s, 6H), 1.3-1.4(m, 5H), 1.6-1.7(m, 2H),1.96(br.t, J=12 Hz, 2H), 2.23(s, 2H), 2.83(br.d, J=12 Hz, 2H), 3.48(s,2H), 7.2-7.4(m, 5H)

Example 225 Methyl 4-(1-benzylpiperidin-4-yl)-3,3-dimethylbutanoate

To a solution of 4.7 g of4-(1-benzylpiperidin-4-yl)-3,3-dimethylbutyronitrile in ethylene glycol(20 ml) was added 30 ml of an aqueous solution of 23 g of potassiumhydroxide and the resulting mixture was reacted at 200° C. for 10 hours.After bringing back to room temperature, water was added to the reactionmixture. Then the reaction mixture was made weakly acidic withhydrochloric acid. After adding ethanol, the solvent was distilled offunder reduced pressure. The crude product thus obtained was suspended in500 ml of methanol and 6.3 ml of thionyl chloride was dropped thereintoat 0° C. After stirring at room temperature for 72 hours, the solventwas distilled off under reduced pressure. Then an aqueous solution ofsodium hydroxide was added to the residue followed by extraction withethyl acetate. The extract was washed with a saturated aqueous solutionof sodium chloride and dried over anhydrous magnesium sulfate. Afterdistilling off the solvent under reduced pressure, the residue waspurified by silica gel column chromatography (eluted with n-hexane/ethylacetate) to thereby give 3.5 g of the title compound as a colorless oilysubstance.

¹H-NMR(CDCl₃) δ ppm: 1.0(s, 6H), 1.2-1.4(m, 5H), 1.55-1.8(m, 2H),1.9-2.0(m, 2H), 2.21(s, 2H), 2.82(br.d, J=12 Hz, 2H), 3.47(s, 2H),3.64(s, 3H), 7.2-7.35(m, 5H)

Example 226 Methyl 3-[1-benzylpiperidin-4-yl]-3-methylbutanoate

Ethyl 2-(1-benzylpiperidin-4-yl)-2-methylpropanoate was treated in thesame manner as those of Examples 222, 223, 224 and 225 to thereby givethe title compound as a yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 0.96(s, 6H), 1.1-1.26(m, 1H), 1.25-1.44(m, 2H),1.56-1.68(m, 2H), 1.84-1.96(m, 2H), 2.23(s, 2H), 2.96(br.d, J=12 Hz,2H), 3.48(s, 2H), 3.64(s, 3H), 7.4-7.65(m, 5H)

Examples 227 to 236

The following compounds were obtained by treating known compounds in thesame manner as the one of Production Example 25.

Ex. Structural formula NMR 227

¹H-NMR (CDCl₃) δ ppm: 1.26(t, J=6Hz, 3H), 1.10- 1.30(m, 2H),1.50-1.60(m, 1H), 1.62-1.76(m, 2H), 1.82(s, 3H), 2.14(t, J=7Hz, 2H),2.70-2.82(m, 2H), 4.10-4.23(m, 2H), 4.18(q, J=6Hz, 2H), 5.12(s, 2H),6.76(t, J=7Hz, 1H), 7.20-7.40(m, 5H) 228

¹H-NMR (CDCl₃) δ ppm: 1.04-2.20(m, 2H), 1.27(t, J=6Hz, 3H), 1.43(s, 9H),1.58-1.70(m, 3H), 2.16(t, J=6Hz, 2H), 2.60-2.75(m, 2H), 4.00-4.18(m,2H), 4.18(q, J=6Hz, 2H), 5.80(d, J=16Hz, 1H), 6.92(dt, J=6, 16Hz, 1H)229

¹H-NMR (CDCl₃) δ ppm: 1.29(t, J=7Hz, 3H), 1.86(s, 3H), 2.36(t, J=6Hz,2H), 2.42-2.52(m, 4H), 2.63(t, J=6Hz, 2H), 3.51(s, 2H), 4.18(q, J=7Hz,2H), 7.2-7.4(m, 5H) 230

¹H-NMR (CDCl₃) δ ppm: 1.26(t, J=7Hz, 3H), 2.73(t, J=7Hz, 2H), 2.92-3.00(m, 2H), 3.26(d, J=1Hz, 2H), 3.65(s, 2H), 4.15(q, J=7Hz, 2H),5.74(t, J=2Hz, 1H), 7.2- 7.4(m, 5H), 231

¹H-NMR (CDCl₃) δ ppm: 1.21(t, J=7Hz, 3H), 1.65- 1.80(m, 2H), 2.23(t,J=6Hz, 2H), 2.50(t, J=6Hz, 2H), 3.61(s, 2H), 3.69(s, 2H), 4.10(q, J=7Hz,2H), 5.67(s, 1H), 7.35(m, 5H) 232

¹H-NMR (CDCl₃) δ ppm: 1.26(t, J=7Hz, 3H), 1.68- 1.76(m, 2H), 2.56(t,J=5Hz, 2H), 2.82-2.88(m, 2H), 2.95(s, 2H), 3.54(s, 2H), 4.14(q, J=7Hz,2H), 5.63(s, 1H), 7.2-7.35(m, 5H) 233

¹H-NMR (CDCl₃) δ ppm: 1.27(t, J=7Hz, 3H), 1.2- 1.34(m, 2H), 1.4-1.7(m,3H), 1.88-1.98(m, 2H), 2.05(d, J=7Hz, 2H), 2.13(d, J=1Hz, 3H),2.87(br.d, J=12Hz, 2H), 3.49(s, 2H), 4.14(q, J=7Hz, 2H), 5.61-5.63(m,1H), 7.2-7.35(m, 5H) 234

¹H-NMR (CDCl₃) δ ppm: 1.21(t, J=7Hz, 3H), 1.28(br.s, 6H), 1.9- 2.4(m,2H), 2.21(br.s, 3H), 2.3-2.5(m, 1H), 2.5- 2.7(m, 2H), 3.65-3.8(m, 1H),4.08(q, J=7Hz, 2H), 5.58(s, 1H) 235

¹H-NMR (CDCl₃) δ ppm: 1.37(t, J=6Hz, 3H), 2.35- 2.50(m, 4H),2.50-2.60(m, 4H), 3.52(s, 2H), 4.35(q, J=6Hz, 2H), 6.30(br.s, 1H),7.18-7.28(m, 3H), 7.28-7.40(m, 4H), 7.86(d, J=7Hz, 2H) 236

¹H-NMR (CDCl₃) δ ppm: 1.00-1.20(m, 2H), 1.29(d, J=7Hz, 3H), 1.20-1.4(m,1H), 1.45(s, 9H), 1.6- 1.7(m, 2H), 1.82(s, 3H), 2.13(t, J=8Hz, 2H),2.60- 2.75(m, 2H), 4.00-4.20(m, 2H), 4.19(q, J=7Hz, 2H), 6.76(t, J=8Hz,1H)

Example 237 Methyl 4-[1-(tert-butoxycarbonyl)piperidin-4-yl]-3-butenoate

3.12 g of maleic acid and one drop of piperidine were added to 50 ml ofxylene and the resulting mixture was heated under reflux for 30 minutes.After adding 2.27 g of[1-(tert-butoxycarbonyl)piperidin-4-yl]acetaldehyde, the resultingmixture was heated under reflux for 2 hours and 20 minutes whileeliminating water with a Dean Stark trap. Then the reaction mixture wasdistributed into diethyl ether and water, washed with a saturatedaqueous solution of sodium chloride and dried over anhydrous magnesiumsulfate. After filtration, the solvent was distilled off under reducedpressure. The obtained residue was dissolved in 150 ml of diethyl etherand treated with a solution of diazomethane in diethyl ether. Afterdistilling off the solvent under reduced pressure, the residue waspurified by silica gel column chromatography (eluted with n-hexane/ethylacetate) to thereby give 0.71 g of the title compound as an oilysubstance.

¹H-NMR(CDCl₃) δ ppm: 1.03-1.25(m, 2H), 1.43(s, 9H), 1.60-1.70(m, 2H),2.03-2.20(m, 2H), 2.55-2.80(m, 2H), 3.00-3.04(m, 1H), 3.67and3.73(s,3H), 4.06(br.s, 2H), 5.43-5.58(m, 2H)

Example 238 1-(tert-Butoxycarbonyl)piperidine-4-spiro-3′-(4′-butanolide)

To a solution of 0.856 g of7-(tert-butoxycarbonyl)-7-azaspiro[3.5]nonan-2-one in dichloromethane(30 ml) was added an aqueous solution of 1.86 g of 3-chloroperbenzoicacid (purity: 50-60%) and 1.20 g of sodium hydrogencarbonate and theresulting mixture was stirred for 18 hours. After adding 50 ml of waterand 50 ml of dichloromethane, the organic layer was dried over magnesiumsulfate, filtered and concentrated under reduced pressure. Then theresidue was purified by silica gel column chromatography (eluted withdichloromethane/ethyl acetate) to thereby give 0.542 g of the titlecompound as white crystals.

¹H-NMR(CDCl₃) δ ppm: 1.45(s, 9H), 1.58(m, 2H), 1.62(t, J=6 Hz, 2H),2.44(s, 2H), 3.26(dt, J=6, 14 Hz, 2H), 3.57(dt, J=6, 14 Hz, 2H), 4.09(s,2H)

Example 239 8-(tert-Butoxycarbonyl)-2-oxa-8-azaspiro[4.5]decan-3-ol

Into a solution of 0.54 g of1-(tert-butoxycarbonyl)-piperidine-4-spiro-3′-(4′-butanolide) indichloromethane (30 ml) was dropped in a nitrogen atmosphere 3.6 ml of a0.93 M solution of diisobutylaluminum hydride in hexane and the reactionmixture was stirred at −70° C. for 3 hours. After adding 1 ml ofmethanol, water and dichloromethane were further added thereto and theinsoluble matters were filtered off. The aqueous layer was extractedwith dichloromethane. The organic layers were combined, dried overmagnesium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (eluted withn-hexane/ethyl acetate) to thereby give 0.43 g of the title compound asa colorless oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.45(s, 9H), 1.52(m, 2H), 1.66(m, 2H), 1.76(dd,J=2, 13 Hz, 1H), 1.99(dd, J=5, 13 Hz, 1H), 2.49(d, J=3 Hz, 1H),3.29-3.48(m, 4H), 3.72(d, J=9 Hz, 1H), 3.84(d, J=9 Hz, 1H), 5.58(m, 1H)

Example 240 Ethyl(E)-4-[1-(tert-butoxycarbonyl)-4-(hydroxymethyl)-piperidin-4-yl]-2-methyl-2-butenoate

By using the same method as the one of Production Example 25, the titlecompound was obtained as an oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.29(t, J=7 Hz, 3H), 1.45(s, 9H), 1.44-1.51(m, 4H),1.87(s, 3H), 2.30(d, J=7 Hz, 2H), 3.25(ddd, J=4, 7, 12 Hz, 2H),3.46(ddd, J=4, 7, 12 Hz, 2H), 3.49(d, J=6 Hz, 2H), 4.19(q, J=7 Hz, 2H),6.81(tq, J=1, 7 Hz, 1H)

Examples 241 to 249

Appropriate ketones synthesized in Examples 188, 190, 189, 187, 184 and195 and appropriate Wittig-Horner-Emons reagents were treated in thesame manner as the one of Production Example 25 to thereby give thefollowing compounds.

Ex. Structural formula NMR 241

¹H-NMR (CDCl₃) δ ppm: 1.27(t, J=7Hz, 3H), 1.46(s, 9H), 1.56- 1.62(m,4H), 2.55(br.s, 2H), 2.87(br.s, 2H), 3.27-3.41(m, 4H), 4.15(q, J=7Hz,2H), 5.69(quint, J=2Hz, 1H) 242

¹H-NMR (CDCl₃) δ ppm: 1.27(t, J=7Hz, 3H), 1.45(s, 9H), 1.50- 1.60(m,4H), 1.71(t, J=1Hz, 3H), 2.50(br.s, 2H), 2.80(br.s, 2H), 3.35(m, 4H),4.16(q, J=7Hz, 2H) 243

¹H-NMR (CDCl₃) δ ppm: 1.27(t, J=7Hz, 3H), 1.44(s, 9H), 2.36- 2.48(m,1H), 2.64- 2.83(m, 4H), 2.98- 3.22(m, 3H), 3.48- 3.60(m, 2H), 4.14(q,J=7.2Hz, 2H), 5.79- 5.83(m, 1H) 244

¹H-NMR (CDCl₃) δ ppm: 1.27(t, J=7.2Hz, 3H), 1.45(s, 9H), 1.90(dt, J=2.4,6.8Hz, 2H), 2.68- 2.86(m, 2H), 2.99-3.19(m, 2H), 3.31-3.43(br.s, 4H),4.08-4.22(m, 2H), 5.67- 5.71(m, 1H) 245

¹H-NMR (CDCl₃) δ ppm: 1.22-1.28(m, 3H), 1.45(s, 9H), 1.53-1.65(m, 2H),1.96-2.06(m, 2H), 2.58- 2.72(m, 3H), 2.78(d, J=1.6Hz, 1H), 2.93(dd,J=2.4, 4.8Hz, 1H), 3.07(d, J=1.6Hz, 1H), 3.17-3.27(m, 2H), 3.38- 3.50(m,2H), 4.08-4.20(m, 2H), 5.61-5.67(m, 1H) 246

¹H-NMR (CDCl₃) δ ppm: 1.24-1.32(m, 3H), 1.49(s, 9H), 1.74-1.86(m, 1H),2.10-2.58(m, 5H), 2.70- 2.78(m, 1H), 3.02-3.46(m, 5H), 4.10-4.18(m, 2H),5.66(s, ½H), 5.73(s, ½H) 247

¹H-NMR (CDCl₃) δ ppm: 1.27(t, J=7.1Hz, 3H), 1.78-1.87(m, 4H), 2.13-2.19(m, 2H), 2.77-2.82(m, 2H), 3.09(s, 4H), 3.68(s, 2H), 4.13(q,J=7.1Hz, 2H), 5.62(s, 1H), 7.23-7.27(m, 1H), 7.28-7.35(m, 4H) 248

¹H-NMR (CDCl₃) δ ppm: 1.08-1.18(m, 3H), 1.23- 1.33(m, 3H), 1.45(s, 9H),1.40-1.80(m, 3H), 2.43- 3.26(m, 5H), 3.91-4.08(m, 1H), 4.10-4.24(m, 3H),4.33-4.50(m, 1H), 5.65- 5.69(m, 1H) 249

¹H-NMR (CDCl₃) δ ppm: 1.28(t, J=6.8Hz, 3H), 1.35-1.48(m, 2H), 1.46(s,9H), 1.64-1.73(m, 2H), 2.03-2.17(m, 1H), 2.15(s, 3H), 2.62-2.76(m, 2H),4.04-4.25(m, 2H), 4.15(q, J=6.8Hz, 2H), 5.66(s, 1H)

Examples 250 to 257

The compounds obtained in Examples 241, 243, 244, 245, 246, 234, 248 and236 were treated in the same manner as the one of Example 20 to therebygive the following compounds.

Ex. Structural formula NMR 250

¹H-NMR (CDCl₃) δ ppm: 1.25(t, J=7Hz, 3H), 1.45(s, 9H), 1.44-1.55(m, 6H),2.04(m, 2H), 2.41(d, J=7Hz, 2H), 2.64(sept, J=7Hz, 1H), 3.25(t, J=6Hz,2H), 3.34(t, J=6Hz, 2H), 4.11(q, J=7Hz, 2H) 251

¹H-NMR (CDCl₃) δ ppm: 1.00-1.13(m, 2H), 1.25(t, J=7Hz, 3H), 1.45(s, 9H),2.08-2.16(m, 2H), 2.24- 2.40(m, 3H), 2.55-2.75(m, 2H), 3.00-3.62(m, 4H),4.13(q, J=7.2Hz, 2H) 252

¹H-NMR (CDCl₃) δ ppm: 1.21-1.28(m, 3H), 1.44 and 1.45(s, total 9H, 5:4),1.64-1.79(m, 2H), 1.84-1.93(m, 1H), 2.05- 2.21(m, 2H), 2.38-2.44(m, 2H),2.58-2.69(m, 1H), 3.14-3.40(m, 5H), 4.07- 4.15(m, 2H) 253

¹H-NMR (CDCl₃) δ ppm: 1.23(t, J=7.2Hz, 3H), 1.40-1.62(m, 3H), 1.44(s,9H), 1.74(dd, J=9.2, 11.2Hz, 1H), 1.81(dd, J=7.6, 12.8Hz, 1H), 1.99-2.14(m, 3H), 2.36 and 2.37(s, total 2H, 2:3), 2.50-2.67(m, 3H),3.06-3.26(m, 2H), 3.36- 3.48(m, 2H), 4.09(q, J=7.2Hz, 2H) 254

¹H-NMR (CDCl₃) δ ppm: 0.88-1.16(m, 2H), 1.24(t, J=6.8Hz, 3H), 1.45(s,9H), 1.50-1.84(m, 4H), 1.90-2.42(m, 5H), 3.08- 3.38(m, 4H), 4.12(q,J=6.8Hz, 2H) 255

¹H-NMR (CDCl₃) δ ppm: 0.86(d, J=7Hz, 6H), 1.25(d, J=7Hz, 3H), 1.69(br.t,J=12Hz, 2H), 1.95-2.05(m, 2H), 2.15(d, J=6Hz, 2H), 2.25(s, 3H),2.2-2.3(m, 1H), 2.51(br.d, J=12Hz, 2H), 4.12(q, J=7Hz, 2H) 256

¹H-NMR (CDCl₃) δ ppm: 1.07 and 1.15(d, J=7.2Hz, total 3H, 1:1), 1.25(t,J=7.2Hz, 3H), 1.45(s, 9H), 1.34-2.00(m, 7H), 2.16-2.94(m, 5H), 3.78-3.94(m, 1H), 4.10(q, J=7.2Hz, 2H), 4.22- 4.37(m, 1H) 257

¹H-NMR (CDCl₃) δ ppm: 1.0-1.7(m, 7H), 1.15(d, J=7Hz, 3H), 1.25(t, J=7Hz,3H), 1.44(s, 9H), 2.36(m, 3H), 2.0-2.7(m, 2H), 4.0-4.2(m, 2H), 4.12(q,J=7Hz, 2H)

Example 258 Ethyl3-[1-(tert-butoxycarbonyl)piperidin-4-yl]cyclobutylacetate

3-[1-(Tert-butoxycarbonyl)piperidin-4-yl]cyclobutan-1-one was treated inthe same manner as those of Production Example 25 and Example 20 tothereby give the title compound.

¹H-NMR(CDCl₃) δ ppm: 0.87-1.00(m, 2H), 1.24(t, J=7.0 Hz, 3H),1.30-1.39(m, 1H), 1.45(s, 9H), 1.53-1.67(m, 4H), 1.73-1.84(m, 1H),1.86-1.97(m, 1H), 2.17-2.26(m, 1H), 2.35(t, J=7.5 Hz, 1H), 2.48(t, J=7.5Hz, 1H), 2.54-2.72(m, 3H), 4.00-4.19(m, 2H), 4.11(q, J=7.0 Hz, 2H)

Example 259 Ethyl 3-[1-(tert-butoxycarbonyl)piperidin-4-yl]butanoate

1-(tert-Butoxycarbonyl)piperidin-4-yl methyl ketone was treated in thesame manner as those of Production Example 25 and Example 20 to therebygive the title compound.

¹H-NMR(CDCl₃) δ ppm: 0.91(d, J=6.8 Hz, 3H), 1.13-1.27(m, 2H), 1.26(t,J=7.0 Hz, 3H), 1.27-1.48(m, 1H), 1.45(s, 9H), 1.53-1.62(m, 2H),1.87-1.95(m, 1H), 2.10(dd, J=8.6, 14.9 Hz, 1H), 2.36(dd, J=4.7, 14.9 Hz,1H), 2.57-2.69(m, 2H), 4.04-4.22(m, 2H), 4.13(q, J=7.0 Hz, 2H)

Example 260 2-TrimethylsilylethylN-(1-benzylpiperidin-4-yl)sulfamoylacetate

Into a solution of 1.586 g of chlorosulfonylacetyl chloride in diethylether (12 ml) was dropped in a nitrogen atmosphere at −10° C. a solutionof 1.060 g of 2-trimethylsilylethanol in diethyl ether (10 ml). Afterstirring at 0° C. for 1 hour, the reaction mixture was concentratedunder reduced pressure and the residue was dissolved in diethyl ether(15 ml) again. Into this solution was dropped a solution of 3.41 g of1-benzyl-4-aminopiperidine in diethyl ether (15 ml) and the resultingmixture was stirred for 20 hours. After adding 50 ml of water and 50 mlof ethyl acetate, the organic layer was dried over magnesium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluted withdichloromethane/methanol) to thereby give 2.21 g of the title compoundas a colorless oily substance.

¹H-NMR(CDCl₃) δ ppm: 0.00(s, 9H), 0.95(m, 2H), 1.59(qd, J=3, 12 Hz, 2H),1.94(br.d, J=12 Hz, 2H), 2.09(br.t, J=12 Hz, 2H), 2.77(br.d, J=12 Hz,2H), 3.31(br.s, 1H), 3.46(s, 2H), 3.92(s, 2H), 4.22(m, 2H), 4.70(br.s,1H), 7.25-7.30(m, 5H)

Example 261 Ethyl4-[1-(tert-butoxycarbonyl)piperidin-4-yl]-2,2-dimethylbutanoate

4.792 g of ethyl4-[1-(tert-butoxycarbonyl)piperidin-4-yl]-2-methylbutanoate was treatedin the same manner as the one of Example 220 to thereby give 4.21 g ofthe title compound as a colorless oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.0-1.20(m, 4H), 1.13(s, 6H), 1.20-1.38(m, 1H),1.22(t, J=6 Hz, 3H), 1.42(s, 9H), 1.48-1.70(m, 4H), 2.58-2.70(m, 2H),4.00-4.10(m, 2H), 4.12(q, J=6 Hz, 2H)

Examples 262 to 265

The ketones obtained in Examples 189, 190, 187 and 195 were treated bythe same method as the one of Production Example 14 to thereby give thefollowing compounds.

Ex. Structural formula NMR 262

¹H-NMR (CDCl₃) δ ppm: 1.45(s, 9H), 1.53(dd, J=6.4, 13.2Hz, 2H), 1.99(dd,J=8.0, 13.2Hz, 2H), 2.48-2.52(m, 2H), 2.57-2.69(m, 4H), 3.22(dd, J=3.2,11.6Hz, 2H), 3.44(dd, J=8.0, 11.6Hz, 2H), 4.74-4.78(m, 2H) 263

¹H-NMR (CDCl₃) δ ppm: 1.46(s, 9H), 1.88(t, J=6.8Hz, 2H), 2.54-2.61(m,2H), 2.64-2.71(m, 2H), 3.32(s, 2H), 3.36(t, J= 6.8Hz, 2H), 4.82-4.86(m,2H) 264

¹H-NMR (CDCl₃) δ ppm: 1.46(s, 9H), 1.42-1.55(m, 1H), 1.67-1.76(m, 1H),1.99-2.08(m, 1H), 2.10- 2.38(m, 5H), 3.06-3.17(m, 1H), 3.18-3.27(m, 1H),3.29-3.40(m, 2H), 4.67(s, 1H), 4.73(s, 1H) 265

¹H-NMR (CDCl₃) δ ppm: 1.11(d, J=7.2Hz, 3H), 1.45(s, 9H), 1.39- 1.49(m,1H), 1.57- 1.74(m, 3H), 2.28- 2.36(m, 1H), 2.44- 2.56(m, 2H), 2.60-2.67(m, 1H), 2.82- 2.91(m, 1H), 3.89- 3.96(m, 1H), 4.30- 4.40(m, 1H),4.77- 4.82(m, 2H)

Examples 266 to 269

The compounds obtained in Examples 262, 263, 264 and 265 were treated inthe same manner as the one of Production Example 72 to thereby give thefollowing compounds.

Ex. Structural formula NMR 266

¹H-NMR (CDCl₃) δ ppm: 1.44(s, 9H), 1.45- 1.62(m, 2H), 1.74- 2.09(m, 6H),2.34- 2.47(m, 1H), 2.52- 2.68(m, 2H), 3.14(dd, J=4.0, 11.2Hz, 1H),3.22(dd, J=3.2, 11.2Hz, 1H), 3.43(dd, J=8.0, 11.2Hz, 2H), 3.58(d,J=9.2Hz, 2H) 267

¹H-NMR (CDCl₃) δ ppm: 1.45 and 1.46(s, total 9H, 1:1), 1.70-1.83(m, 3H),1.89(t, J=6.8Hz, 1H), 1.96-2.10(m, 2H), 2.43-2.63(m, 1H), 3.21(s, 1H),3.28- 3.38(m, 2H), 3.34(s, 1H), 3.62 and 3.63(d, J=4.0Hz, total 2H, 1:1)268

¹H-NMR (CDCl₃) δ ppm: 0.87-1.34(m, 2H), 1.44- 1.83(m, 5H), 1.46(s, 9H),1.97-2.13(m, 1H), 2.31-2.47(m, 1H), 3.15- 3.23(m, 2H), 3.29- 3.39(m,2H), 3.47(d, J=3.2Hz, 1H), 3.48(d, J=2.8Hz, 1H) 269

¹H-NMR (CDCl₃) δ ppm: 1.09(d, J=7.2Hz, 1H), 1.16(d, J=7.2Hz, 2H),1.36-1.90(m, 7H), 1.45(s, 9H), 2.03-2.23(m, 1H), 2.42-2.54(m, 1H), 2.81-2.97(m, 1H), 3.58-3.64(m, 2H), 3.80-3.95(m, 1H), 4.24-4.38(m, 1H)

Example 270 4-Allyl-1-(tert-butoxycarbonyl)piperidin-4-ol

Into a solution of 4.98 g of 1-(tert-butoxycarbonyl)-4-piperidone indiethyl ether (150 ml) was dropped at 0° C. in a nitrogen atmosphere 30ml of a 1.0 M solution of allylmagnesium bromide in diethyl ether andthe resulting mixture was stirred for 3 hours. Then the reaction mixturewas poured into an aqueous solution of sodium dihydrogenphosphate andextracted with ethyl acetate. The organic layer was dried over anhydrousmagnesium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (eluted withn-hexane/ethyl acetate) to thereby give 4.12 g of the title compound asa white solid.

¹H-NMR(CDCl₃) δ ppm: 1.45(s, 9H), 1.54(m, 4H), 2.23(br.d, J=7 Hz, 2H),3.15(br.s, 2H), 3.80(br.s, 2H), 5.15(ddt, J=1, 2, 16 Hz, 1H), 5.21(ddt,J=1, 2, 10 Hz, 1H), 5.86(ddt, J=7, 10, 16 Hz, 1H)

Example 2714-(2,3-Epoxypropan-1-yl)-1-(tert-butoxycarbonyl)piperidin-4-ol

To a solution of 4.115 g of4-allyl-1-(tert-butoxycarbonyl)piperidin-4-ol in dichloromethane (100ml) were added 7.07 g of 3-chloroperbenzoic acid and 2.87 g of sodiumhydrogencarbonate and the resulting mixture was heated under reflux for24 hours. To the reaction mixture were added ethyl acetate and anaqueous solution of sodium metabisulfite and the resulting mixture wasstirred for 1 hour. The organic layer was dried over anhydrous magnesiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (eluted withdichloromethane/ethyl acetate) to thereby give 1.43 g of the titlecompound as a colorless solid.

¹H-NMR(CDCl₃) δ ppm: 1.45(s, 9H), 1.40-1.56(m, 5H), 1.88(dd, J=3, 14 Hz,1H), 2.00(br.s, 1H), 2.50(dd, J=3, 6 Hz, 1H), 2.82(t, J=3 Hz, 1H),3.14-3.27(m, 3H), 3.91(br.s, 2H)

Example 272[7-(tert-Butoxycarbonyl)-1-oxa-7-azaspiro[3.5]non-2-yl]methanol

To a solution of 1.42 g of4-(2,3-epoxypropan-1-yl)-1-(tert-butoxycarbonyl)piperidin-4-ol indimethyl sulfoxide (20 ml) were added in a nitrogen atmosphere 5 ml ofwater and 2.32 g of lithium hydroxide and the resulting mixture washeated to 140° C. for 30 minutes. After adding ethyl acetate, thereaction mixture was washed with water thrice. The organic layer wasdried over anhydrous magnesium sulfate, filtered and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluted with dichloromethane/ethyl acetate) to therebygive 0.336 g of the title compound as colorless crystals.

¹H-NMR(CDCl₃) δ ppm:1.46(s, 9H), 1.72-1.85(m, 3H), 1.91(m, 1H), 1.97(dd,J=5, 8 Hz, 1H)2.26(dd, J=7, 10 Hz, 1H), 2.37(dd, J=8, 10 Hz, 1H),3.32-3.52(m, 3H), 3.57(ddd, J=4, 8, 11 Hz, 1H), 3.78(ddd, J=3, 4, 11 Hz,1H), 4.75(m, 1H)

Examples 273 to 276

The compounds obtained in Examples 266, 267, 269 and 272 were treated inthe same manner as the one of Production Example 73 to thereby give thefollowing compounds.

Ex. Structural formula NMR 273

¹H-NMR (CDCl₃) δ ppm: 1.45(s, 9H), 1.44-1.50(m, 1H), 1.52- 1.59(m, 1H),1.84-1.92(m, 1H), 1.98-2.08(m, 4H), 2.25-2.31(m, 1H), 2.55- 2.70(m, 2H),3.04-3.28(m, 3H), 3.39-3.47(m, 2H), 9.71 and 9.72(s, total 1H, 1:1) 274

¹H-NMR (CDCl₃) δ ppm: 1.45 and 1.46(s, total 9H, 1:1), 1.78 and 1.92(t,J=6.8Hz, total 2H, 1:1), 2.06-2.35(m, 4H), 3.06- 3.43(m, 5H), 9.74 and9.77(d, J=2.0Hz, total 1H, 1:1) 275

¹H-NMR (CDCl₃) δ ppm: 1.10 and 1.14(d, J=7.2Hz, total 3H, 1:2), 1.32-1.42(m, 1H), 1.45(s, 9H), 1.45-2.27(m, 7H), 2.80- 2.96(m, 1H),3.08-3.24(m, 1H), 3.81-4.00(m, 1H), 4.25- 4.40(m, 1H), 9.73 and 9.78(dJ=1.6Hz, total 1H, 1:2) 276

¹H-NMR (CDCl₃) δ ppm: 1.45(s, 9H), 1.66-2.01(m, 4H), 2.24-2.36(m, 2H),3.47-3.51(m, 4H), 4.65(t, J=7Hz, 1H), 9.80(s, 1H)

Example 277[3-(tert-Butoxycarbonyl)-3-azabicyclo[3.3.0]oct-7-yl]-carbaldehyde

3-(tert-Butoxycarbonyl)-3-azabicyclo [3.3.0]octan-7-one was successivelytreated by the procedures of Production Examples 71, 72 and 73 tothereby give the title compound.

¹H-NMR(CDCl₃) δ ppm: 1.44(s, 9H), 1.65-1.77(m, 2H), 2.06-2.18(m, 2H),2.63-2.75(m, 2H), 2.81-2.91 and 2.95-3.04(m, total 1H, 2:1),3.12-3.23(m, 2H), 3.43-3.56(m, 2H), 9.62-9.64(m, 1H)

Examples 278 to 282

The aldehydes obtained in Examples 277, 273, 274, 276 and 275 weretreated in the same manner as that of Production Example 74 to therebygive the following compounds.

Ex. Structural formula NMR 278

¹H-NMR(CDCl₃) δ ppm: 1.44(s, 9H), 1.65-1.84(m, 2H), 2.03- 2.23(m, 2H),2.56-3.02(m, 3H), 3.02-3.59(m, 4H), 3.67(s, 3H) 279

¹H-NMR(CDCl₃) δ ppm: 1.45(s, 9H), 1.46-1.56(m, 2H), 1.88- 1.96(m, 1H),2.01-2.19(m, 4H), 2.28-2.35(m, 1H), 2.53-2.69(m, 2H), 3.03(quint,J=8.8Hz, 1H), 3.11-3.18(m, 1H), 3.20- 3.28(m, 1H), 3.40-3.47(m, 2H),3.67(s, 3H) 280

¹H-NMR(CDCl₃) δ ppm: 1.42-1.52(m, 9H), 1.81- 1.93(m, 2H), 2.10-2.38(m,4H), 3.04-3.14(m, 1H), 3.22-3.46(m, 4H), 3.69(s, 3H) 281

¹H-NMR(CDCl₃) δ ppm: 1.46(s, 9H), 1.76(m, 2H), 1.95(m, 2H), 2.46(dd,J=7, 11Hz, 1H, 2.66(dd, J=9, 11Hz, 1H), 3.36-3.54(m, 4H), 3.80(s, 3H),5.00(dd, J=7, 9Hz, 1H) 282

¹H-NMR(CDCl₃) δ ppm: 1.08 and 1.14(d, J=7.2Hz, total 3H), 1.45(s, 9H),1.56-1.83(m, 4H), 1.87- 2.11(m, 2H), 2.17- 2.37(m, 2H), 2.81- 2.94(m,1H), 3.04- 3.16(m, 1H), 3.68 and 3.69(s, total 3H), 3.81-3.98(m, 1H),4.24- 4.38(m, 1H)

Example 283 Methyl [8-(tert-butoxycarbonyl)-8-azabicyclo[4.3.0]non-3-yl-carboxylate

[8-(tert-Butoxycarbonyl)-8-azabicyclo [4.3.0]non-3-yl]methanol wassuccessively treated by the same methods as those of Production Examples73 and 74 to thereby give the title compound.

¹H-NMR(CDCl₃) δ ppm: 1.46(s, 9H), 1.24-1.95(m, 6H), 2.03-2.14(m, 1H),2.24-2.52(m, 2H), 3.14-3.25(m, 2H), 3.31-3.42(m, 2H), 3.67(s, 3H)

Example 284 Methyl (3-benzyloxycarbonyl-3-azabicyclo[4.1.0]hept-6-yl)acetate

1.41 g of oxalyl chloride was dissolved in 70 ml of dichloromethane andcooled to −78° C. in a nitrogen atmosphere. Then a solution of 1.38 g ofdimethyl sulfoxide in dichloromethane (3 ml) was dropped thereinto over5 minutes. Further, a solution of 1.22 g of(3-benzyloxycarbonyl-3-azabicyclo[4.1.0]hept-6-yl)ethanol indichloromethane (10 ml) was dropped thereinto over 5 minutes. Afterstirring the mixture for 15 minutes, 2.24 g of triethylamine was droppedthereinto over 5 minutes and stirring was continued for additional 30minutes. Then the reaction mixture was diluted with dichloromethane,washed with 1 N hydrochloric acid and a saturated aqueous solution ofsodium chloride and dried over anhydrous magnesium sulfate. Afterfiltration, the solvent was distilled off under reduced pressure and theresidue was purified by silica gel column chromatography (eluted withn-hexane/ethyl acetate) to thereby give 450 mg of a product. Thisproduct was dissolved in 6 ml of dimethyl sulfoxide and 5 ml of anaqueous solution of 257 mg of sodium dihydrogenphosphate was addedthereto. Further, 5 ml of an aqueous solution of 496 mg of sodiumchlorite was added thereto over 5 minutes and the resulting mixture wasstirred at room temperature for 10 minutes. Next, the reaction mixturewas diluted with ethyl acetate, washed successively with water and asaturated aqueous solution of sodium chloride, dried over anhydrousmagnesium sulfate and filtered. After distilling off the solvent underreduced pressure, the obtained residue was dissolved in 40 ml oftoluene. After adding 6 ml of a 2 M solution oftrimethylsilyldiazomethane in hexane and 10 ml of methanol, theresulting mixture was stirred at room temperature for 50 minutes. Thenthe reaction mixture was concentrated under reduced pressure and theobtained residue was purified by silica gel column chromatography(eluted with ethyl acetate/methanol) to thereby give 180 mg of the titlecompound as a colorless oily substance.

¹H-NMR(CDCl₃) δ ppm: 0.41-0.48(m, 1H), 0.54-0.66(m, 1H), 0.88-1.04(m,1H), 1.76-1.92(m, 2H), 2.16-2.42(m, 2H), 3.15-3.24(m, 1H), 3.32-3.44(m,1H), 3.60-3.68(m, 1H), 3.68(s, 3H), 3.80-3.88(m, 1H), 5.10(s, 2H),7.28-7.40(m, 5H)

Example 285[7-(tert-Butoxycarbonyl)-7-azaspiro[3.5]non-2-yl]carbonitrile

2.39 g of [7-(tert-butoxycarbonyl)-7-azaspiro[3.5]nonan-2-one wastreated in the same manner as the one of Production Example 34 tothereby give 0.99 g of the title compound as colorless crystals.

¹H-NMR(CDCl₃) δ ppm: 1.45(s, 9H), 1.55(dd, J=5, 6 Hz, 2H), 1.62(dd, J=5,6 Hz, 2H), 2.18(m, 2H), 2.25(m, 2H), 3.17(m, 1H), 3.32(m, 4H)

Example 286 (7-Benzyl-7-azaspiro[3.5]non-2-yl)carbonitrile

To a solution of 1.44 g of[7-(tert-butoxycarbonyl)-7-azaspiro[3.5]non-2-yl]carbonitrile indichloromethane (40 ml) was added 10 ml of trifluoroacetic acid and theresulting mixture was stirred at room temperature for 2.5 hours. Then anaqueous solution of disodium hydrogenphosphate was added to the reactionmixture followed by extraction with ethyl acetate and dichloromethane.The extract was dried over anhydrous magnesium sulfate and then thesolvent was concentrated under reduced pressure. Thus 0.935 g of crude(7-azaspiro[3.5]non-2-yl)carbonitrile was obtained. This crude productwas dissolved in 40 ml of dichloromethane. After adding at 0° C. 0.94 gof triethylamine and 1.27 g of benzyl bromide, the resulting mixture wasstirred at room temperature for 12 hours. To the reaction mixture wasadded an aqueous solution of disodium hydrogenphosphate. Then theresulting mixture was extracted with ethyl acetate and dried overanhydrous magnesium sulfate. After distilling off the solvent underreduced pressure, the residue was purified by silica gel columnchromatography (eluted with methanol/dichloromethane) to thereby give1.12 g of the title compound as a colorless oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.60(t, J=5 Hz, 2H), 1.69(t, J=5 Hz, 2H), 2.13(dd,J=8, 12 Hz, 2H), 2.21(J=10, 12 Hz, 2H), 2.31(br.s, 4H), 3.02(m, 1H),3.44(s, 2H), 7.22-7.33(m, 5H)

Example 287 Methyl(7-benzyl-7-azaspiro[3.5]non-2-yl)carboxylate

(7-Benzyl-7-azaspiro[3.5]non-2-yl)carbonitrile was treated in the samemanner as the one of Production Example 35 to thereby give the titlecompound.

¹H-NMR(CDCl₃) δ ppm: 1.58(t, J=5 Hz, 2H), 1.64(t, J=5 Hz, 2H), 2.00(s,2H), 2.02(s, 2H), 2.28(br.s, 2H), 2.34(br.s, 2H), 3.04(quint, J=9 Hz,1H), 3.43(s, 2H), 3.67(s, 3H), 7.22-7.33(m, 5H)

Example 288 Methyl4-[1-(benzyloxycarbonyl)piperidin-4-yloxy]phenylacetate

1-(Benzyloxycarbonyl)piperidin-4-ol and methyl 4-hydroxyphenylacetatewere treated in the same manner as the one of Production Example 65 tothereby give the title compound as a pale green powder.

¹H-NMR(CDCl₃) δ ppm: 1.73-1.83(m, 2H), 1.86-1.96(m, 2H), 3.42-3.50(m,2H), 3.56(s, 2H), 3.69(s, 3H), 3.70-3.78(m, 2H), 4.47(m, 1H), 5.14(s,2H), 6.83-6.88(m, 2H), 7.17-7.21(m, 2H), 7.29-7.38(m, 5H)

Example 289 Methyl4-[1-(benzyloxycarbonyl)piperidin-4-yl]methyloxy]-phenylacetate

[1-(Benzyloxycarbonyl)piperidin-4-yl]methanol and methylp-hydroxyphenylacetate were treated in the same manner as the one ofProduction Example 65 to thereby give the title compound as a pale greenpowder.

¹H-NMR(CDCl₃) δ ppm: 1.22-1.35(m, 2H), 1.80-1.88(m, 2H), 1.98(m, 1H),2.76-2.89(m, 2H), 3.56(s, 2H), 3.68(s, 3H), 3.78(d, J=6.4 Hz, 2H),4.15-4.32(m, 2H), 5.14(s, 2H), 6.81-6.86(m, 2H), 7.16-7.21(m, 2H),7.29-7.38(m, 5H)

Example 290 Ethyl 1-(1-benzylpiperidin-4-yl)cyclopropane carboxylate

13 ml of diisopropylamine was dissolved in a solvent mixture oftetrahydrofuran (140 ml) with HMPA (15 ml) in a nitrogen atmosphere andcooled to −78° C. Into the obtained solution was dropped 42 ml of a 2.5M solution of n-butyllithium in hexane and the resulting mixture wasstirred at 0° C. for 30 minutes. After cooling to −78° C. again, 15 mlof a solution of 5.8 g of ethyl (1-benzylpiperidin-4-yl)acetate intetrahydrofuran was dropped thereinto. The reaction mixture was stirredat 0° C. for 1 hour. Then 1,2-dibromoethane was dropped thereinto at−78° C. again. The reaction mixture was stirred at 0° C. for 30 minutesand then brought back to room temperature. Next, it was distributed intowater and ethyl acetate. The organic layer was extracted, washed withwater and dried over magnesium sulfate. After distilling off the solventunder reduced pressure, the residue was purified by silica gel columnchromatography (eluted with n-hexane/ethyl acetate) to thereby give 1.40g of ethyl 2-(1-benzyl-4-piperidyl)-4-bromobutanoate as a colorless oilysubstance. A solution of 1.40 g of ethyl2-(1-benzyl-4-piperidyl)-4-bromobutanoate in tetrahydrofuran (20 ml) wasstirred at room temperature and 1.0 g of t-butoxypotassium was addedthereto. The reaction mixture was distributed into water and ethylacetate. The organic layer was extracted and washed with water. Afterdistilling off the solvent under reduced pressure, the obtained residuewas purified by silica gel column chromatography (eluted withn-hexane/ethyl acetate) to thereby give 800 mg of the title compound asa colorless oily substance.

¹H-NMR(CDCl₃) δ ppm: 0.74(dd, J=3.9, 6.7 Hz, 2H), 1.08(dd, J=3.9, 6.7Hz, 2H), 1.22(t, J=7.0 Hz, 3H), 1.32-1.44(m, 2H), 1.52-1.59(m, 2H),1.70-1.79(m, 1H), 1.90-1.99(m, 2H), 2.87-2.93(m, 2H), 3.48(s, 2H),4.19(q, J=7.0 Hz, 2H), 7.20-7.33(m, 5H)

Example 291 Ethyl[2-methyl-7-(tert-butoxycarbonyl)-7-azaspiro[3.5]non-2-yl]acetate

To a suspension of 2.85 g of cuprous iodide in diethyl ether was addedin a nitrogen atmosphere at 23° C. 22 ml of a 1.4 M solution ofmethyllithium in diethyl ether. After stirring at −23° C. for 30minutes, the mixture was cooled to −75° C. Into this solution wasdropped 20 ml of a solution of 0.927 g of ethyl7-(tert-butoxycarbonyl)-7-azaspiro[3.5]non-2-ylidene]acetate andtrimethylsilyl chloride in diethyl ether. The bulk temperature waselevated to room temperature and the reaction mixture was stirred for 15hours. After adding 100 ml of ethyl acetate and sodium hydrogencarbonatethereto, the insoluble matters were filtered off, dried over anhydrousmagnesium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (eluted withdichloromethane/methanol) to thereby give 0.609 g of the title compoundas white crystals.

¹H-NMR(CDCl₃) δ ppm: 1.22(s, 3H), 1.25(t, J=7 Hz, 3H), 1.44(s, 9H),1.49(m, 2H), 1.56(m, 2H), 1.71(d, J=13 Hz, 2H), 1.88(d, J=13 Hz, 2H),2.39(s, 2H), 3.29(m, 4H), 4.14(q, J=7 Hz, 2H)

Example 292 1-Benzylpiperidin-4-ylideneethyl vinyl ether

To a solution of 1.08 g of (1-benzylpiperidin-4-ylidene)ethanol in vinylethyl ether (30 ml) was added in a nitrogen atmosphere 0.107 g ofmercurous trifluoroacetate. After stirring at room temperature for 18hours, 10 ml of a 10% aqueous solution of sodium hydroxide was addedthereto and the resulting mixture was extracted with n-hexane (50 ml).The organic layer was washed with an aqueous solution of sodium chloride(3×10 ml), dried over anhydrous magnesium sulfate and concentrated underreduced pressure to thereby give 1.153 g of the title compound as acolorless oily substance.

¹H-NMR(CDCl₃) δ ppm: 2.24(t, J=5 Hz, 2H), 2.32(t, J=6 Hz, 2H), 2.45(tt,J=5, 6 Hz, 4H), 3.51(s, 2H), 4.01(d, J=5 Hz, 2H), 4.18-4.23(m, 2H),5.38(t, J=5 Hz, 1H), 6.47(dd, J=9, 15 Hz, 1H), 7.34-7.36(m, 5H)

Example 293 (1-Benzyl-4-vinylpiperidin-4-yl)acetaldehyde

A solution of 0.82 g of (1-benzylpiperidin-4-ylidene)-ethyl vinyl etherin benzonitrile (30 ml) was degassed in a nitrogen atmosphere and heatedto 190° C. for 1 hour. Then the reaction mixture was concentrated underreduced pressure and the residue was purified by silica gel columnchromatography (eluted with dichloromethane/methanol) to thereby give0.67 g of the title compound as a colorless oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.66-1.72(m, 2H), 1.78-1.83(m, 2H), 2.37-2.41(m,2H), 2.40(s, 2H), 2.47-2.54(m, 2H), 3.48(s, 2H), 5.07(d, J=16 Hz, 1H),5.24(d, J=10 Hz, 1H), 5.84(dd, J=10, 16 Hz, 1H), 7.31-7.35(m, 5H),9.71(s, 1H)

Example 294 Methyl (1-benzyl-4-vinylpiperidin-4-yl)acetate

To a solution of 0.486 g of (1-benzyl-4-vinylpiperidin-4-yl)acetaldehydein N,N-dimethylformamide (10 ml) were added 0.48 g of methanol and 4.50g of pyridinium dichromate and the resulting mixture was stirred at roomtemperature for 20 hours. After adding 100 ml of diethyl ether, thereaction mixture was filtered through celite. After concentrating underreduced pressure, the residue was purified by silica gel columnchromatography (eluted with dichloromethane/methanol) to thereby give0.321 g of the title compound as a colorless oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.66(m, 2H), 1.78-1.84(m, 2H), 2.30-2.35(m, 2H),2.37(s, 2H), 2.49-2.55(m, 2H), 3.48(s, 2H), 3.61(s, 3H), 5.01(d, J=17Hz, 1H), 5.15(d, J=11 Hz, 1H), 5.76(dd, J=11, 17 Hz, 1H), 7.30-7.32(m,5H)

Example 295 4-(1-Benzyl-4-hydroxypiperidin-4-yl)benzaldehyde

Starting with 0.74 g of magnesium, 6.42 g of 4-bromobenzaldehydedimethyl acetal and 50 ml of tetrahydrofuran, a Grignard reagent wasprepared in a conventional manner. Then it was ice-cooled and 10 ml of asolution of 5.67 ml of 1-benzyl-4-piperidone in tetrahydrofuran wasdropped thereinto in such a manner that the bulk temperature did notexceed 20° C. After stirring at room temperature for 1 hour, 50 ml of asaturated aqueous solution of ammonium chloride was added thereto andthen 1 N-hydrochloric acid was added until the pH value reached about 2.After stirring for 1 hour, the reaction mixture was concentrated underreduced pressure and the tetrahydrofuran was distilled off. To theresidue were added anhydrous potassium carbonate and ethyl acetate andthe resulting mixture was stirred for 15 minutes. The organic layer wasseparated, washed with water and a saturated aqueous solution of sodiumchloride and dried over anhydrous sodium sulfate. After distilling offthe solvent under reduced pressure, the residue was purified by silicagel column chromatography (eluted with n-hexane/ethyl acetate) tothereby give 4.27 g of the title compound as a slightly yellow solid.

¹H-NMR(CDCl₃) δ ppm: 1.69-1.78(m, 3H), 2.18(dt, J=4.6, 13.3 Hz, 2H),2.47(dt, J=2.6, 13.3 Hz, 2H), 2.79-2.86(m, 2H), 3.59(s, 2H),7.25-7.29(m, 1H), 7.31-7.38(m, 4H), 7.68-7.72(m, 2H), 7.85-7.89(m, 2H),10.00(s, 1H)

Example 296 4-(1-Benzyl-4-hydroxypiperidin-4-yl)-2-methoxybenzaldehydedimethyl acetal

15.0 g of 4-bromo-2-methoxybenzaldehyde dimethyl acetal was dissolved in150 ml of ether and the obtained solution was cooled to −50° C. Then25.3 ml of a 1.6 M solution of n-butyllithium in hexane was droppedthereinto. 1 hour thereafter, 30 ml of a solution of 11.7 ml of1-benzyl-4-piperidone in diethyl ether was dropped thereinto in such amanner that the bulk temperature did not exceed −35° C. After stirringat room temperature for 50 minutes, water was added thereto followed byextraction with ethyl acetate. The organic layer was washed with waterand a saturated aqueous solution of sodium chloride and dried overanhydrous sodium sulfate. After distilling off the solvent under reducedpressure, 23.82 g of a pale yellow oily substance was obtained. 13.82 gof this oily substance was purified by silica gel column chromatography(eluted with dichloromethane/methanol) to thereby give 6.31 g of thetitle compound as a pale yellow solid.

¹H-NMR(CDCl₃) δ ppm: 1.59(s, 1H), 1.68-1.76(m, 2H), 2.11-2.22(m, 2H),2.42-2.52(m, 2H), 2.77-2.84(m, 2H), 3.36(s, 6H), 3.59(s, 2H), 3.86(s,3H), 5.64(s, 1H), 7.01-7.11(m, 2H), 7.24-7.29(m, 2H) 7.31-7.38(m, 3H),7.48(dd, J=0.5, 7.7 Hz, 1H)

Example 297 4-(1-Benzyl-4-hydroxypiperidin-4-yl)-2-methoxybenzaldehyde

To 10.0 g of 4-(1-benzyl-4-hydroxypiperidin-4-yl)-2-methoxybenzaldehydedimethyl acetal were added 100 ml of toluene and 6.15 g ofp-toluenesulfonic acid monohydrate and the resulting mixture was heatedunder reflux for 1 hour. To the reaction mixture were added water andtriethylamine followed by extraction with ethyl acetate. The organiclayer was washed with water and a saturated aqueous solution of sodiumchloride and dried over anhydrous sodium sulfate. After distilling offthe solvent under reduced pressure, the residue was purified by silicagel column chromatography (eluted with dichloromethane/methanol) tothereby give 3.43 g of the title compound as a pale brown oilysubstance.

¹H-NMR(CDCl₃) δ ppm: 1.67-1.78(m, 3H), 2.13-2.22(m, 2H), 2.41-2.50(m,2H), 2.79-2.87(m, 2H), 3.60(s, 2H), 3.94(s, 3H), 7.14(ddd, J=0.7, 1.6,8.1 Hz, 1H), 7.22(d, J=1.6 Hz, 1H), 7.24-7.38(m, 5H), 7.80(d, J=8.1 Hz,1H), 10.4(s, 1H)

Example 2984-[1-Benzyl-4-(3-methoxy-4-[2-methylthio-2-(methylsulfinyl)-vinyl]phenyl]piperidin-4-ol

3.43 g of 4-(1-benzyl-4-hydroxypiperidin-4-yl)-2-methoxybenzaldehyde wasdissolved in 30 ml of tetrahydrofuran. To the resulting solution wereadded 2.42 ml of methyl methylsulfinylmethyl sulfoxide and 2 ml of a 40%solution of benzyltrimethylammonium hydroxide in methanol and theresulting mixture was heated under reflux for 3 hours. Afterconcentrating the reaction mixture, water was added thereto followed byextraction with ethyl acetate. The organic layer was washed with waterand a saturated aqueous solution of sodium chloride and dried overanhydrous sodium sulfate. After distilling off the solvent under reducedpressure, the residue was purified by silica gel column chromatography(eluted with dichloromethane/methanol) to thereby give 4.58 g of thetitle compound as a pale yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.71-1.78(m, 2H), 1.94(br.s, 1H), 2.13-2.23(m, 2H),2.29(s, 3H), 2.44-2.53(m, 2H), 2.75(s, 3H), 2.79-2.85(m, 2H), 3.60(s,2H), 3.85(s, 3H), 7.10-7.14(m, 2H), 7.24-7.39(m, 5H), 7.95(s, 1H),8.12(d, J=8.6 Hz, 1H)

Example 2994-[1-Benzyl-4-[4-[2-methylthio-2-(methylsulfinyl)vinyl]phenyl-piperidin-4-ol

The title compound was obtained as a pale yellow oily substance by thesame method as the one of Example 298.

¹H-NMR(CDCl₃) δ ppm: 1.70-1.78(m, 3H), 2.13-2.23(m, 2H), 2.32(s, 3H),2.44-2.52(m, 2H), 2.76(s, 3H), 2.78-2.84(m, 2H), 3.59(s, 2H),7.30-7.38(m, 4H), 7.56-7.60(m, 2H), 7.60(s, 1H), 7.58-7.91(m, 2H)

Example 300 Methyl4-(1-benzyl-4-hydroxypiperidin-4-yl)-2-methoxyphenyl-acetate

4.58 g of4-[1-benzyl-4-[3-methoxy-4-[2-methylthio-2-(methylsulfinyl)vinyl]phenyl]piperidin-4-olwas dissolved in 100 ml of a 10% solution of hydrogen chloride inmethanol and the solution was heated under reflux for 1 hour and 40minutes. Then the reaction mixture was concentrated under reducedpressure. After adding an aqueous solution of sodium carbonate, themixture was extracted with ethyl acetate. The organic layer was washedwith water and a saturated aqueous solution of sodium chloride and driedover anhydrous sodium sulfate. After distilling off the solvent underreduced pressure, 3.41 g of the title compound was obtained as aslightly brown oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.58(br.s, 1H), 1.69-1.76(m, 2H), 2.11-2.21(m, 2H),2.43-2.51(m, 2H), 2.77-2.83(m, 2H), 3.59(s, 2H), 3.61(s, 2H), 3.69(s,3H), 3.82(s, 3H), 7.03(dd, J=1.8, 7.7 Hz, 1H), 7.07(d, J=1.8 Hz, 1H),7.15(d, J=7.7 Hz 1H), 7.24-7.38(m, 5H)

Example 301 Methyl 4-(1-benzyl-4-hydroxypiperidin-4-yl)phenylacetate

The title compound was obtained as a pale yellow oily substance by thesame method as the one of Example 300.

¹H-NMR(CDCl₃) δ ppm: 1.54(br.s, 1H), 1.69-1.76(m, 2H), 2.15(dt, J=4.6,13.2 Hz, 2H), 2.47(dt, J=2.6, 13.2 Hz, 2H), 2.75-2.82(m, 2H)3.58(s, 2H),3.62(s, 2H), 3.69(s, 3H), 7.24-7.28(m, 3H), 7.30-7.38(m, 4H),7.46-7.49(m, 2H)

Example 302 Methyl4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)-2-methoxy-phenylacetate

3.41 g of methyl4-(1-benzyl-4-hydroxypiperidin-4-yl)-2-methoxyphenylacetate wasdissolved in 50 ml of toluene. After adding 3.5 g of p-toluenesulfonicacid monohydrate, the mixture was heated under reflux for 1 hour and 45minutes. After adding water and triethylamine, the reaction mixture wasextracted with dichloromethane and the organic layer was dried overanhydrous sodium sulfate. After distilling off the solvent under reducedpressure, 3.6 g of a pale yellow oily substance was obtained.

This product was dissolved in 100 ml of a 10% solution of hydrogenchloride in methanol and heated under reflux for 2 hours. The reactionmixture was concentrated under reduced pressure. After adding an aqueoussolution of sodium hydrogencarbonate, the mixture was extracted withethyl acetate. The organic layer was washed with water and a saturatedaqueous solution of sodium chloride and dried over anhydrous sodiumsulfate. After distilling off the solvent under reduced pressure, theresidue was purified by silica gel column chromatography (eluted withdichloromethane/methanol) to thereby give 2.28 g of the title compoundas a pale yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 2.52-2.58(m, 2H), 2.71(t, J=5.9 Hz, 2H), 3.17(dd,J=2.7, 5.9 Hz, 2H), 3.61(s, 2H), 3.64(s, 2H), 3.68(s, 3H), 3.81(s, 3H),6.04(m, 1H), 6.88(d, J=1.6 Hz, 1H), 6.93(dd, J=1.6, 7.7 Hz, 1H), 7.11(d,J=7.7 Hz, 1H), 7.24-7.40(m, 5H)

Example 303 [1-[1-tert-Butoxycarbonyl)piperidin-4-yl]butan-1-one oxime

3.1 g of [1-(1-tert-butoxycarbonyl)piperidin-4-yl]butan-1-one wasdissolved in 20 ml of ethanol. After adding 1 g of hydroxylaminehydrochloride and 1.5 g of sodium acetate, the resulting mixture washeated under reflux for 2.5 hours. The reaction mixture was concentratedunder reduced pressure and water was added to the residue followed byextraction with ethyl acetate. The organic layer was washed with waterand dried over anhydrous magnesium sulfate. After distilling off thesolvent under reduced pressure, the residue was purified by silica gelcolumn chromatography (eluted with n-hexane/ethyl acetate) to therebygive 2.3 g of the title compound as white crystals.

¹H-NMR(CDCl₃) δ ppm: 0.96(t, J=7.2 Hz, 3H), 1.40-1.60(m, 5H), 1.45(s,9H), 1.69-1.80(m, 2H), 2.22-2.33(m, 2H), 2.62-2.78(m, 2H), 4.03-4.25(m,2H)

Example 304 Ethyl[(1-(tert-butoxycarbonyl)piperidin-4-yl]butan-1-yl]iminoxyacetate

2.3 g of [1-[1-tert-butoxycarbonyl)piperidin-4-yl]butan-1-one oxime wasdissolved in 10 ml of N,N-dimethylformamide and ice-cooled. After adding0.41 g of 70% sodium hydride, 1.1 ml of ethyl bromoacetate was furtheradded and the resulting mixture was stirred for 1 hour. After addingice-water, the reaction mixture was extracted with ethyl acetate. Theorganic layer was washed with water and a saturated aqueous solution ofsodium chloride and dried over anhydrous magnesium sulfate. Afterdistilling off the solvent under reduced pressure, the residue waspurified by silica gel column chromatography (eluted with n-hexane/ethylacetate) to thereby give 2.47 g of the title compound as a pale yellowoily substance.

¹H-NMR(CDCl₃) δ ppm: 0.96(t, J=7.6 Hz, 3H), 1.27(t, J=7.2 Hz, 3H),1.37-1.60(m, 5H), 1.46(s, 9H), 1.65-1.77(m, 2H), 2.23-2.31(m, 2H),2.64-2.78(m, 2H), 4.04-4.26(m, 2H), 4.20(q, J=7.2 Hz, 2H), 4.55(s, 2H)

Example 305 Ethyl[(1-tert-butoxycarbonyl)piperidin-4-yl]-2-hydroxyacetate

To a solution of 6.1 g of diisopropylamine in tetrahydrofuran (60 ml)was added a 1.6 M solution of 38 ml of n-butyllithium in hexane and theresulting mixture was stirred at 0° C. for 30 minutes. After cooling thereaction mixture to −70° C., a solution of 10.6 g of ethyl[1-(tert-butoxycarbonyl)piperidin-4-yl]acetate in tetrahydrofuran (40ml) was dropped thereinto. After 1 hour, 26 g of MoPH[peroxymolybdenum(pyridine)(hexamethylphosphorous triamide)]was addedthereto and the resulting mixture was slowly heated to room temperatureover 5 hours. After adding water, the reaction mixture was extractedwith ethyl acetate. The organic layer was washed with water and asaturated aqueous solution of sodium chloride and dried over anhydrousmagnesium sulfate. After distilling off the solvent under reducedpressure, the residue was purified by silica gel column chromatography(eluted with n-hexane/ethyl acetate) to thereby give 3.9 g of the titlecompound as a pale yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.32(t, J=7.2 Hz, 3H), 1.39-1.45(m, 2H), 1.45(s,9H), 1.60-1.67(m, 2H), 1.82-1.93(m, 1H), 2.59-2.74(m, 2H), 2.75(d, J=6.0Hz, 1H), 4.05(dd, J=3.5, 6.0 Hz, 1H), 4.08-4.25(m, 2H), 4.27(q, J=7.2Hz, 2H)

Example 306 Ethyl [(1-(tert-butoxycarbonyl)piperidin-4-yl]-2-oxoacetate

By the same method as the one of Production Example 73, the titlecompound was obtained as a pale yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.38(t, J=7.2 Hz, 3H), 1.45(s, 9H), 1.47-1.62(m,2H), 1.84-1.93(m, 2H), 2.79-2.93(m, 2H), 3.16-3.25(m, 1H), 4.03-4.17(m,2H), 4.33(q, J=7.2 Hz, 2H)

Example 307 Ethyl [(1-benzylpiperidin-4-yl)carbamoyl]aminoacetate

2 g of 4-amino-1-benzylpiperidine was dissolved in 15 ml oftetrahydrofuran. After adding 1.6 g of ethyl isocyanatoacetate, theresulting mixture was heated under reflux for 1 hour. Then the reactionmixture was concentrated under reduced pressure to thereby give 3.15 gof the title compound as white crystals.

¹H-NMR(CDCl₃) δ ppm: 1.28(t, J=7.2 Hz, 3H), 1.41-1.52(m, 2H),1.88-1.97(m, 2H), 2.07-2.17(m, 2H), 2.77-2.86(m, 2H), 3.51(s, 2H),3.52-3.65(m, 1H), 3.97(d, J=5.2 Hz, 2H), 4.20(q, J=7.2 Hz, 2H),4.52(br.d, J=8.5 Hz, 1H), 5.39(br.t, J=5.2 Hz, 1H), 7.22-7.35(m, 5H)

Example 308 Ethyl [4-(tert-butoxycarbonyl)aminopiperidin-1-yl]acetate

2 g of 4-(tert-butoxycarbonyl)aminopiperidine was dissolved in 50 ml ofdichloromethane. After adding 1.6 ml of triethylamine and 1.2 ml ofethyl bromoacetate, the resulting mixture was stirred at roomtemperature for 5 hours. The reaction mixture was washed with water anddried over anhydrous magnesium sulfate. After distilling off the solventunder reduced pressure, the residue was purified by silica gel columnchromatography (eluted with dichloromethane/methanol) to thereby give3.0 g of the title compound as pale yellow crystals.

¹H-NMR(CDCl₃) δ ppm: 1.27(t, J=7.2 Hz, 3H), 1.44(s, 9H), 1.44-1.58(m,2H), 1.88-1.97(m, 2H), 2.21-2.32(m, 2H), 2.85-2.95(m, 2H), 3.20(s, 2H),3.42-3.53(m, 1H), 4.18(q, J=7.2 Hz, 2H), 4.39-4.49(m, 1H)

Examples 309 to 312

Similar to Example 308, 4-(tert-butoxycarbonyl)amino-piperidine wastreated with a halogenated fatty acid ester or an acid halide to therebygive the following compounds.

Ex. Structural formula NMR 309

¹H-NMR (CDCl₃) δ ppm: 1.25 (t, J = 7.2 Hz, 3H), 1.35-1.52 (m, 2H), 1.45(s, 9H), 1.87-1.97 (m, 2H), 2.08-2.18 (m, 2H), 2.49 (t, J = 7.4 Hz, 2H),2.70 (t, J = 7.4 Hz, 2H), 2.78-2.88 (m, 2H), 3.41-3.52 (m, 1H), 4.13 (q,J = 7.2 Hz, 2H), 4.37-4.47 (m, 1H) 310

¹H-NMR (CDCl₃) δ ppm: 1.25 (t, J = 7.2 Hz, 3H), 1.37-1.49 (m, 2H), 1.43(s, 9H), 1.81 (quint, J = 7.4 Hz, 2H), 1.87-1.97 (m, 2H), 2.05-2.14 (m,2H), 2.32 (t, J = 7.4 Hz, 2H), 2.37 (t, J = 7.4 Hz, 2H), 2.80-2.89 (m,2H), 3.40-3.54 (m, 1H), 4.11 (q, J = 7.2 Hz, 2H), 4.39-4.49 (m, 1H) 311

¹H-NMR (CDCl₃) δ ppm: 1.25-1.40 (m, 2H), 1.29 (t, J = 7.2 Hz, 3H), 1.45(s, 9H), 1.93-2.07 (m, 2H), 2.73-2.83 (m, 1H), 3.12-3.20 (m, 1H), 3.44(d, J = 14.7 Hz, 1H), 3.48 (d, J = 14.7 Hz, 1H), 3.62-3.76 (m, 2H), 4.20(q, J = 7.2 Hz, 2H), 4.43- 4.57 (m, 2H) 312

¹H-NMR (CDCl₃) δ ppm: 1.33-1.42 (m, 2H), 1.36 (t, J = 7.2 Hz, 3H), 1.44(s, 9H), 1.97-2.07 (m, 2H), 2.82-2.90 (m, 1H), 3.12-3.20 (m, 1H),3.61-3.77 (m, 2H), 4.32 (q, J = 7.2 Hz, 2H), 4.36-4.52 (m, 2H)

Example 313 EthylN-(methanesulfonyl)-N-(1-benzylpiperidin-4-yl)aminoacetate

By the same method as those of Examples 308 and 316, the title compoundwas obtained as a pale yellow oily substance from 1-benzylpiperidine.

¹H-NMR(CDCl₃) δ ppm: 1.28(t, J=7.2 Hz, 3H), 1.57-1.70(m, 2H),1.77-1.84(m, 2H), 2.01-2.11(m, 2H), 2.91-2.98(m, 2H), 3.10(s, 3H),3.49(br.s, 2H), 3.59-3.69(m, 1H), 4.01(s, 2H), 4.17(q, J=7.2 Hz, 2H),7.23-7.35(m, 5H)

Example 314 4-Aminomethyl-1-benzylpiperidine

To a solution of 2.2 g of 1-benzylisonipecotamide in 50 ml oftetrahydrofuran was added 1.58 g of lithium aluminum hydride at 0° C.and the resulting mixture was heated under reflux for 2 hours. Then thereaction mixture was cooled to 0° C. After adding water and a 10%aqueous solution of sodium hydroxide, the insoluble matters werefiltered off. After distilling off the solvent under reduced pressure,2.0 g of the title compound was obtained as a brown oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.2-1.4(m, 3H), 1.4-1.8(m, 2H), 1.8-1.9(m, 2H),1.94(br.t, J=10 Hz, 2H), 2.56(d, J=5 Hz, 2H), 2.90(d, J=10 Hz, 2H),3.49(s, 2H), 7.2-7.4(m, 5H)

Example 315 2-(1-Benzylpiperidin-4-yl)ethylamine

By the same method of the one of Example 314, 0.5 g of(1-benzylpiperidin-4-ylidene)acetonitrile was treated to thereby give0.5 g of the title compound as a brown oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.2-1.4(m, 6H), 1.5-1.7(m, 2H), 1.93(br.t, J=10 Hz,2H), 2.71(t, J=8 Hz, 1H), 2.87(br.d, J=10 Hz, 2H), 3.46(s, 2H),7.2-7.4(m, 5H)

Example 316 N-(1-Benzylpiperidin-4-yl)methanesulfonamide

To a solution of 5.0 g of 4-amino-1-benzylpiperidine in 100 ml ofdichloromethane were added 4.1 ml of pyridine and 2.2 ml ofmethanesulfonyl chloride at 0° C. Then the mixture was reacted at thesame temperature for 1 hour. The reaction mixture was poured into water,extracted with ethyl acetate, washed with a saturated aqueous solutionof sodium chloride and dried over anhydrous magnesium sulfate. Afterdistilling off the solvent under reduced pressure, the crystals thusprecipitated were taken up by filtration to thereby give 7.0 g of thetitle compound as colorless crystals.

¹H-NMR(DMSO-d₆) δ ppm: 1.36-1.48(m, 2H), 1.77(br.d, J=11 Hz, 2H),1.96(t, J=12 Hz, 2H), 2.70(br.d, J=12 Hz, 2H), 2.88(s, 3H), 3.0-3.16(m,1H), 3.40(s, 2H), 7.03(d, J=7 Hz, 1H), 7.18-7.34(m, 5H)

Examples 317 to 325

The procedure of Example 316 was repeated by using known acid chloridesor acid anhydrides as a substitute for the methanesulfonyl chloride tothereby give the following compounds.

Ex. Structural formula NMR 317

¹H-NMR (DMSO-d₆) δ ppm: 1.5-1.63 (m, 2H), 1.70-1.85 (m, 2H), 2.75-2.95(m, 2H), 3.20- 3.40 (m, 3H), 3.43-3.65 (m, 2H), 7.20-7.40 (m, 5H), 9.45(s, 1H) 318

¹H-NMR (DMSO-d₆) δ ppm: 1.7-2.2 (m, 4H), 2.61 (s, 6H), 2.9-3.4 (m, 7H),7.41 (br.s, 4H), 7.58 (br.s, 2H) 319

¹H-NMR (CDCl₃) δ ppm: 2.46-2.56 (m, 4H), 2.82 (s, 6H), 3.24-3.32 (m,4H), 3.54 (br.s, 2H), 7.24-7.37 (m, 5H) 320

¹H-NMR (DMSO-d₆) δ ppm: 1.34-1.50 (m, 2H), 1.7-1.84 (m, 2H), 1.84-1.96(m, 2H), 2.40 (d, J = 5 Hz, 3H), 2.66-2.76 (m, 2H), 2.84-2.96 (m, 1H),3.40 (s, 2H), 6.58 (d, J = 5 Hz, 1H), 6.85 (d, J = 5 Hz, 1H), 7.18-7.33(m, 5H) 321

¹H-NMR (CDCl₃) δ ppm: 1.2-1.35 (m, 2H), 1.4-1.6 (m, 1H), 1.71 (d, J = 13Hz, 2H), 1.95 (t, J = 13 Hz, 2H), 2.90 (d, J = 10 Hz, 2H), 2.94 (s, 3H),3.00 (t, J = 8 Hz, 2H), 3.49 (s, 2H), 4.4-4.6 (m, 1H), 7.2-7.35 (m, 5H)322

¹H-NMR (CDCl₃) δ ppm: 1.2-1.34 (m, 2H), 1.4-1.56 (m, 1H), 1.6-1.7 (m,2H), 1.88- 1.98 (m, 2H), 2.00 (s, 3H), 2.84-2.94 (m, 2H), 3.13 (t, J = 6Hz, 2H), 3.48 (s, 2H), 5.5-5.6 (m, 1H), 7.2-7.4 (m, 5H) 323

¹H-NMR (CDCl₃) δ ppm: 1.2-1.4 (m, 5H), 1.43-1.55 (m, 2H), 1.64 (br.d, J= 10 Hz, 2H), 1.93 (br.t, J = 10 Hz, 2H), 2.86 (br.d, J = 10 Hz, 2H),2.93 (s, 3H), 3.15 (t, J = 5 Hz, 1H), 3.46 (s, 2H), 7.2-7.4 (m, 5H) 324

¹H-NMR (CDCl₃) δ ppm: 1.1-1.4 (m, 5H), 1.4 (m, 2H), 1.5-1.8 (m, 2H),1.8-2.2 (m, 2H), 1.95 (s, 3H), 2.87 (br.d, J = 10 Hz, 2H), 3.2-3.3 (m,1H), 3.48 (s, 2H), 7.2-7.4 (m, 5H) 325

¹H-NMR (CDCl₃) δ ppm: 2.59 (m, 1H), 2.95 (m, 2H), 2.98 (s, 3H), 3.26 (t,J = 7 Hz, 2H), 3.37 (m, 2H), 4.34 (s, 1H), 5.04 (br.s, 1H), 7.07-7.38(m, 10H)

Example 326 N-(1-Benzylpiperidin-4-yl)sulfamide

To a solution of 3.0 g of 4-amino-1-benzylpiperidine in dimethoxyethane(20 ml) was added 1.35 g of sulfamide. The resulting mixture was stirredat 100° C. for 10 minutes and then reacted at 130° C. for 1 hour. Afterdistilling off the solvent under reduced pressure, 4.0 g of the titlecompound was obtained as a brown oily substance.

¹H-NMR(DMSO-d₆) δ ppm: 1.35-1.50(m, 2H), 1.7-1.9(m, 2H), 1.9-2.1(m, 2H),2.7-2.85(m, 2H), 3.0-3.1(m, 1H), 3.45(s, 2H), 6.46(s, 2H), 6.54(d, J=6Hz, 1H), 7.2-7.4(m, 5H)

Example 327 N²-Methanesulfonyl-N¹-(piperidin-4-yl)formamidine

Into a solution of 760 mg of ethyl N-methanesulfonyl-formimidate indiethyl ether (20 ml) was dropped 0.95 g of 4-amino-1-benzylpiperidineat room temperature. After stirring for 2 hours, the crystals thusprecipitated were filtered and washed with diethyl ether to thereby give580 mg of N²-methanesulfonyl-N¹-(1-benzylpiperidin-4-yl)formamidine ascolorless needles. These crystals were dissolved in 30 ml of methanoland 500 mg of 10% palladium-carbon was added thereto. Then the resultingmixture was stirred in a hydrogen atmosphere under atmospheric pressurefor 1 hour followed by filtration through celite. After distilling offthe solvent under reduced pressure, the residue was recrystallized fromacetone/ethyl acetate to thereby give 310 mg of the title compound ascolorless needles.

¹H-NMR(DMSO-d₆) δ ppm: 1.26(dq, J=4.1, 12.5 Hz, 2H), 1.73(br.d, J=12.5Hz, 2H), 2.44(br.t, J=12.5 Hz, 2H), 2.83(s, 3H), 2.85(br.d, J=12.5 Hz,2H), 3.60-3.70(br.m, 1H), 7.84(s, 1H), 8.64-8.73(br.s, 1H)

Example 328 N,N-(4-Benzylpiperazin-1-ylmethylene)methanesulfonamide

Into a solution of 1.51 g of ethyl N-methanesulfonyl-formimidate indiethyl ether/tetrahydrofuran (50%, 5 ml) was dropped a solution of 1.76g of 1-benzylpiperazine in diethyl ether/tetrahydrofuran (50%, 50 ml)and the resulting mixture was reacted at 40° C. for 1 hour. Afterallowing to cool, the crystals thus precipitated were taken up byfiltration and washed with diethyl ether to thereby give 2.7 g of thetitle compound as colorless crystals.

¹H-NMR(CDCl₃) δ ppm: 2.48(t, J=5.0 Hz, 2H), 2.52(t, J=5.0 Hz, 2H),2.95(s, 3H), 3.47(t, J=5.0 Hz, 2H), 3.55(s, 2H), 3.68(t, J=5.0 Hz, 2H),7.27-7.38(m, 5H), 8.06(s, 1H)

Example 329 N-(1-Benzylpiperidin-4-yl)amidinocarboxylic acid

A solution of 1.9 g of 4-amino-1-benzylpiperidine in dichloromethane (40ml) was stirred in a nitrogen atmosphere and 20 ml of a solution ofbenzyl 2-ethylthio-2-iminoacetate in dichloromethane was droppedthereinto. Then the resulting mixture was stirred for 30 minutes and thesolvent was distilled off under reduced pressure. To the obtainedresidue in the form of a colorless oily substance were added 50 ml ofmethanol and 50 ml of water. Then about 1 g of Dowex (HCO₃-form) whichhad been preliminarily conditioned was added thereto. After stirring for1 hour, the resulting mixture was filtered and the Dowex-1 was wellwashed with methanol. After distilling off the solvent under reducedpressure, 2.3 g of the title compound was obtained as a colorlesspowder.

¹H-NMR(DMSO-d₆) δ ppm: 1.40-1.58(m, 1H), 1.60-1.70(m, 3H), 1.88-2.02(m,2H), 2.71-2.83(m, 2H), 3.37-3.52(m, 1H), 3.43(s, 2H), 7.19-7.33(m, 5H),8.62-8.69(br.s, 1H), 8.72-8.79(br.s, 1H), 8.88-8.96(br.s, 1H)

Example 330 Methyl 1-benzylpiperidine-4-carboximidate dihydrochloride

A solution of 20 g of 1-benzylpiperidine-4-carbonitrile in a mixture ofdry dichlolomethane (200 ml) with methanol (30 ml) was cooled andsaturated with a hydrogen chloride gas while maintaining the reactionsystem at 0° C. or below. After allowing to stand for 4 hours at 0° C.,the solvent was distilled off under reduced pressure at room temperatureor below and the residue was diluted with ethyl acetate. The colorlesscrystals thus obtained were ground, filtered and washed with ethylacetate to thereby give 23.6 g of the title compound.

¹H-NMR(CD₃OD) δ ppm: 2.12(br.q, J=13.1 Hz, 2H), 2.23(br.d, J=13.1 Hz,2H), 3.07-3.16(br.m, 1H), 3.18(br.t, J=13.1 Hz, 2H), 3.58(br.d, J=13.1Hz, 2H), 4.18(s, 3H), 4.36(s, 2H), 7.46-7.53(m, 3H), 7.55-7.63(m, 2H)

Example 331 N²-methanesulfonyl(piperidin-4-yl)carboxamidine

6.1 g of methyl 1-benzylpiperidine-4-carboximidate dihydrochloride wasdistributed into an aqueous solution of potassium carbonate and ethylacetate under ice-cooling. The organic layer was extracted and driedover anhydrous sodium sulfate. After distilling off the solvent underreduced pressure, 4.7 g of free methyl1-benzylpiperidine-4-carboximidate was obtained as a colorless oilysubstance. A solution of 2.35 g of methyl1-benzylpiperidine-4-carboximidate and 0.95 g (10 mmol) ofmethanesulfonamide in dry methanol was stirred at room temperature for 3days. Subsequently, 1.0 g of palladium-carbon was added to the reactionmixture and the resulting mixture was stirred in a hydrogen atmosphereunder atmospheric pressure for 1 hour. The inorganic matters wereeliminated by filtering through celite. After distilling off the solventunder reduced pressure, the residue was recrystallized from methanol tothereby give 1.38 g of the title compound as colorless needles.

¹H-NMR(DMSO-d₆) δ ppm: 1.43(dq, J=4.1, 12.8 Hz, 2H), 1.56(br.d, J=12.8Hz, 2H), 2.21-2.31(m, 1H), 2.38(br.t, J=12.8 Hz, 2H), 2.83(s, 3H),2.91(br.d, J=12.8 Hz, 2H), 7.51-7.65(br.s, 1H), 8.27-8.39(br.s, 1H)

Example 332 N²-Methanesulfonyl(4-benzylpiperazin-1-yl)carboxamidine

A solution of 2.52 g of 2-methyl-3-methanesulfonylisothiourea and 1.76 gof 1-benzylpiperazine in toluene (10 ml) and tetrahydrofuran (5 ml) washeated under reflux in a nitrogen atmosphere for 5 days. (In the courseof this heating treatment, 2.52 g of2-methyl-3-methanesulfonylisothiourea and 1.76 g of 1-benzylpiperazinewere further added thereto). After distilling off the solvent underreduced pressure from the reaction mixture, the obtained residue waspurified by silica gel column chromatography (eluted withdichloromethane/methanol). After recrystallizing from diisopropyl ether,1.7 g of the title compound was obtained as colorless crystals.

¹H-NMR(CDCl₃) δ ppm: 2.46(t, J=5.0 Hz, 4H), 2.95(s, 3H), 3.48(t, J=5.0Hz, 4H), 3.53(s, 2H), 6.02-6.16(br.s, 2H), 7.25-7.37(m, 5H)

Example 333 N-(Piperidin-4-yl)benzenesulfonamide

4-Amino-1-benzylpiperidine was treated successively by the same methodsas those of Examples 316 and 20 to thereby give 7.0 g of the titlecompound as a pale yellow oily substance.

¹H-NMR(DMSO-d₆) δ ppm: 1.43-1.60(m, 2H), 1.60-1.75(m, 2H), 2.78-2.90(m,2H), 3.05-3.15(m, 2H), 3.2-3.4(m, 1H), 7.55-7.65(m, 3H), 7.81(d, J=8 Hz,2H), 8.0(m, 1H)

Example 334 4-[1-(tert-Butoxycarbonyl)piperidin-4-yl]-2-butenenitrile

The title compound was obtained as a pale yellow oily substance by thesame method as the one of Production Example 25.

¹H-NMR(CDCl₃) δ ppm: 1.45(s, 9H), 1.62(m, 4H), 2.08(t, J=7 Hz, 2H),2.39(m, 1H), 2.70(br.s, 2H), 4.05(br.s, 2H), 5.32 and 5.38(dt, J=2, 16Hz and 2, 10 Hz, 1H trans/cis≈2:1), 6.50 and 6.66(dt, J=7, 10 Hz and 7,16 Hz, 1H cis/trans≈1:2)

Example 335 4-[1-(tert-Butoxycarbonyl)piperidin-4-yl]butyronitrile

The title compound was obtained as a pale yellow oily substance by thesame method as the one of Example 20.

¹H-NMR(CDCl₃) δ ppm: 1.10(m, 2H), 1.41(m, 3H), 1.45(s, 9H), 1.56(m, 4H),2.34(t, J=7 Hz, 2H), 2.65(m, 2H), 4.08(br.s, 2H)

Example 336 N-Methyl-2-(piperidin-4-yl)ethanesulfonamide acetate

500 mg of N-methyl-2-(piperidin-4-yl)ethanesulfonamide was dissolved in15 ml of acetic acid. After adding 180 mg of platinum oxide, theresulting mixture was subjected to catalytic reduction at roomtemperature under a hydrogen pressure of 6 atm. After filtering off theinsoluble matters, the acetic acid was distilled off under reducedpressure. The crystals thus precipitated were well washed with diethylether and dried under reduced pressure. Thus 664 mg of the titlecompound was obtained as white crystals almost quantitatively.

¹H-NMR(CDCl₃) δ ppm: 1.55(br.q, J=12 Hz, 2H), 1.72-1.78(m, 3H), 1.84(d,J=12 Hz, 2H),1.88(s,3H),2.55(s,3H),2.62(br.s,2H),2.93-3.04(m,4H),6.89(br.s,1H)

Example 337 N,N-Dimethyl-2-(piperidin-4-yl)ethanesulfonamide acetate

The title compound was obtained as white crystals by the same method asthe one of Example 336.

¹H-NMR(CDCl₃) δ ppm: 1.18(q, J=12 Hz, 2H), 1.46-1.58(m, 3H), 1.71(br.d,J=12 Hz, 2H), 1.78(s, 3H), 2.58(br.t, J=12 Hz, 2H), 2.74(s, 6H), 3.01(m,2H), 3.06(m, 2H)

Example 338[5-[1-(tert-Butoxycarbonyl)piperidin-4-yl]-3-oxo-2-methyl-4-penten-2-yl]acetate

The title compound was obtained as a colorless oily substance bytreating [1-(tert-butoxycarbonyl)piperidin-4-yl]carbaldehyde and(4-diethylphosphono-3-oxo-2-methylbutan-2-yl]acetate by the same methodas the one of Production Example 25.

¹H-NMR(CDCl₃) δ ppm: 1.33(br.d, J=13 Hz, 2H), 1.46(s, 9H), 1.48(s, 6H),1.72(br.d, J=13 Hz, 2H), 2.07(s, 3H), 2.29(m, 1H), 2.76(t, J=12 Hz, 2H),4.11(br.s, 2H), 6.31(dd, J=2, 16 Hz, 1H), 6.97(dd, J=7, 16 Hz, 1H)

Example 339[5-[1-(tert-Butoxycarbonyl)piperidin-4-yl]-3-oxo-2-methyl-pentan-2-yl]acetate

The title compound was obtained as a colorless oily substance bytreating[5-[1-(tert-butoxycarbonyl)piperidin-4-yl]-3-oxo-2-methyl-4-penten-2-yl]acetateby the same method as the one of Example 20.

¹H-NMR(CDCl₃) δ ppm: 1.08(qd, J=4, 12 Hz, 2H), 1.34-1.42(m, 1H), 1.45(s,9H), 1.46(s, 6H), 1.51-1.56(m, 2H), 1.60-1.65(br.d, J=12 Hz, 2H),2.08(s, 3H), 2.45(t, J=7 Hz, 2H), 2.66(t, J=11 Hz, 2H), 4.06(br.s, 2H)

Example 340[5-[1-(tert-Butoxycarbonyl)piperidin-4-yl]-2-hydroxy-2-methyl]-3-pentanone

The title compound was obtained as a colorless oily substance bytreating[5-[1-(tert-butoxycarbonyl)piperidin-4-yl]-3-oxo-2-methylpentan-2-yl]acetateby the same method as the one of Production Example 96.

¹H-NMR(CDCl₃) δ ppm: 1.10(qd, J=4, 12 Hz, 2H), 1.37(s, 6H), 1.45(s, 9H),1.35-1.58(m, 3H)1.64(d, J=12 Hz, 2H), 2.67(t, J=8 Hz, 2H), 2.75(m, 2H),3.74(s, 1H), 4.08(br.s, 2H)

Example 341 3-(tert-Butoxycarbonyl)-3-azabicyclo[3.3.0]octan-7-ol

386 mg of ³-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]-octan-7-onesynthesized in accordance with the method described in Tetrahedron, 49,5047 (1993) was dissolved in 20 ml of ethanol. After adding 65 mg ofsodium borohydride, the resulting mixture was stirred at roomtemperature for 30 minutes. Then the reaction mixture was concentratedunder reduced pressure, diluted with ethyl acetate, washed with waterand a saturated aqueous solution of sodium chloride and then dried overanhydrous magnesium sulfate. After filtering, the solvent was distilledoff under reduced pressure and the residue was purified by silica gelcolumn chromatography (eluted with n-hexane/ethyl acetate) to therebygive 319 mg of the title compound as white crystals.

¹H-NMR(CDCl₃) δ ppm: 1.42-1.55(m, 2H), 1.45(s, 9H), 1.69(s, 1H),2.12-2.22(m, 2H), 2.54-2.66(m, 2H), 3.34(dd, J=3.6, 11.2 Hz, 2H),3.49(dd, J=8.0, 11.2 Hz, 2H), 4.29(q, J=6.4 Hz, 1H)

Example 342 Methyl1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydro-4-pyridinecarboxylate

4.62 g of methyl 1-benzyl-1,2,3,6-tetrahydro-4-pyridinecarboxylate wasdissolved in 30 ml of dichloromethane. Under ice-cooling, 4.29 g of1-chloroethyl chloroformate was added thereto and the resulting mixturewas heated under reflux for 2 hours. After adding 50 ml of methanol, themixture was stirred at 70° C. for 1 hour and 20 minutes. Thentriethylamine was added to the reaction mixture under ice-cooling untilthe pH value of the mixture exceeded 7. After further adding 4.37 g oftert-butyl dicarbonate, the resulting mixture was stirred at roomtemperature for 10 minutes. Then the reaction mixture was concentratedunder reduced pressure, diluted with ethyl acetate, washed successivelywith water and a saturated aqueous solution of sodium chloride and driedover anhydrous magnesium sulfate. After filtration, the solvent wasdistilled off under reduced pressure and the obtained residue waspurified by silica gel column chromatography (eluted with n-hexane/ethylacetate) to thereby give 4.46 g of the title compound as a yellow oilysubstance.

¹H-NMR(CDCl₃) δ ppm: 1.47(s, 9H), 2.40(br.s, 2H), 3.51(t, J=5.6 Hz, 2H),3.76(s, 3H), 4.07(d, J=2.4 Hz, 2H), 6.88(br.s, 1H)

Example 3431-(tert-Butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-methanol

17.6 g of methyl1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydro-4-pyridinecarboxylate wasdissolved in 300 ml of tetrahydrofuran. After adding 4.77 g of lithiumtetrahydroborate and then 20 ml of methanol, the resulting mixture wasstirred at room temperature for 20 minutes. Saturated ammonium chloridewas added to the reaction mixture under ice-cooling and the resultingmixture was concentrated under reduced pressure. The residue was dilutedwith ethyl acetate, washed successively with water and a saturatedaqueous solution of sodium chloride and dried over anhydrous magnesiumsulfate followed by filtration. After distilling off the solvent underreduced pressure, the obtained residue was purified by silica gel columnchromatography (eluted with n-hexane/ethyl acetate) to thereby give 10.7g of the title compound as a colorless oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.47(s, 9H), 1.64(br.s, 1H), 2.08-2.16(m, 2H),3.47-3.58(m, 2H), 3.91(br.s, 2H), 4.06(br.s, 2H), 5.64(br.s, 1H)

Example 344[3-(tert-Butoxycarbonyl)-3-azabicyclo[4.1.0]hept-6-yl]methanol

Under ice-cooling, 15.3 ml of diethylzinc and 6.7 g of diiodomethanewere added to 130 ml of dichloromethane. After further adding a solutionof 1.07 g of1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-methanol indichloromethane (20 ml), the resulting mixture was stirred at roomtemperature overnight. Then the reaction mixture was poured intosaturated ammonium chloride, extracted with ethyl acetate, washed with asaturated aqueous solution of sodium chloride and dried over anhydrousmagnesium sulfate followed by filtration. After distilling off thesolvent under reduced pressure, the obtained residue was purified bysilica gel column chromatography (eluted with n-hexane/ethyl acetate) tothereby give 90 mg of the title compound as a colorless oily substance.

¹H-NMR(CDCl₃) δ ppm: 0.38(t, J=5.2 Hz, 1H), 0.58and0.60(d, J=5.2 Hz,total1H), 0.92-1.00(m, 1H), 1.08-1.20(m, 1H), 1.44(s, 9H),1.93and1.97(t, J=5.6 Hz, total1H), 3.06and3.09(dd, J=5.2, 8.4 Hz,total1H), 3.37-3.43(m, 2H), 3.51and3.55(d, J=5.2 Hz, total1H),3.58and3.72(d, J=1.6 Hz, total1H), 4.08-4.17(m, 1H)

Example 345 Ethyl [1-(tert-butoxycarbonyl)piperidin-4-ylidene]acetate

51.0 g of ethyl (1-benzylpiperidin-4-ylidene)acetate was dissolved in200 ml of dichloroethane. After adding 36.5 g of 1-chloroethylchloroformate under ice-cooling, the resulting mixture was heated underreflux for 2 hours. After adding 100 ml of methanol, the resultingmixture was further heated under reflux for 40 minutes and then allowedto stand at room temperature overnight. Then 60 g of triethylamine wasadded to the reaction mixture under ice-cooling. Further, 300 ml ofmethanol was added thereto and the system was made homogeneous. Next,47.2 g of tert-butyl dicarbonate was added and the resulting mixture wasstirred at room temperature for 20 minutes. The reaction mixture wasconcentrated under reduced pressure, diluted with ethyl acetate, washedsuccessively with 1 N hydrochloric acid, water, a saturated aqueoussolution of sodium chloride and saturated sodium hydrogencarbonate anddried over anhydrous magnesium sulfate followed by filtration. Afterdistilling off the solvent under reduced pressure, the crude crystalsthus obtained were ground and washed with hexane to thereby give 15.2 gof the title compound. The filtrate was concentrated and the residue waspurified by silica gel column chromatography (eluted with n-hexane/ethylacetate) to thereby give 37.8 g of the additional title compound ascolorless crystals.

¹H-NMR(CDCl₃) δ ppm: 1.28(t, J=7.2 Hz, 3H), 1.47(s, 9H), 2.25-2.31(m,2H), 2.91-2.96(m, 2H), 3.45-3.53(m, 4H), 4.15(q, J=7.2 Hz, 2H), 5.71(t,J=1.2 Hz, 1H)

Example 346 Ethyl[1-(tert-buxycarbonyl)-1,2,3,6-tetrahydro-pyridin-4-yl]acetate

53.0 g of ethyl [1-(tert-butoxycarbonyl)-piperidin-4-ylidene]acetate wasdissolved in 400 ml of toluene. After adding 3 g of1,8-diazabicyclo[5.4.0]-7-undecene, the resulting mixture was heatedunder reflux for 4 days. After concentrating the reaction mixture underreduced pressure, the residue was purified by silica gel columnchromatography (eluted with n-hexane/ethyl acetate) to thereby give 31.9g of the title compound as a colorless oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.27(t, J=7.2 Hz, 3H), 1.46(s, 9H), 2.12-2.37(m,2H), 3.02(s, 2H), 3.51(t, J=6.0 Hz, 2H), 3.88-3.92(m, 2H), 4.15(q, J=7.2Hz, 2H)5.52(br.s, 1H)

Example 3472-[1-(tert-Butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]ethanol

The title compound was obtained as a colorless oily substance bytreating ethyl[1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]acetate by thesame method as the one of Example 343.

¹H-NMR(CDCl₃) δ ppm: 1.47(s, 9H), 2.05-2.12(m, 2H), 2.24-2.32(m, 2H),3.50(t, J=6.0 Hz, 2H), 3.71(t, J=6.0 Hz, 2H), 3.86-3.90(m, 2H),5.46-5.51(m, 1H)

Example 348 2-[1-(Benzyloxycarbonyl)-1,2,3,6-tetrahydropyridin-4-ylethanol

11.76 g of 2-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)ethanol wasdissolved in 100 ml of tetrahydrofuran. After adding 100 ml of a 4 Nsolution of hydrogen chloride in dioxane, the resulting mixture wasstirred at room temperature for 8 hours and 20 minutes. Then thereaction mixture was concentrated under reduced pressure and the residuewas dissolved in a mixture of tetrahydrofuran (100 ml) with a 4 Nsolution of sodium hydroxide (70 ml). Under ice-cooling, 9.7 g ofbenzyloxycarbonyl chloride was dropped thereinto over 25 minutes and theresulting mixture was stirred for 40 minutes. The reaction mixture wasconcentrated under reduced pressure, diluted with ethyl acetate, washedwith a saturated aqueous solution of sodium chloride and dried overanhydrous magnesium sulfate followed by filtration. After distilling offthe solvent under reduced pressure, the obtained residue was purified bysilica gel column chromatography (eluted with n-hexane/ethyl acetate) tothereby give 11.4 g of the title compound as a colorless oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.62(s, 1H), 2.11(br.s, 2H), 2.29(t, J=6.0 Hz, 2H),3.59(t, J=6.0 Hz, 2H), 3.71(t, J=6.0 Hz, 2H), 3.95-4.00(m, 2H), 5.15(s,2H), 5.49(br.s, 1H), 7.15-7.20(m, 5H)

Example 3492-[3-(Benzyloxycarbonyl)-3-azabicyclo[4.1.0]hept-6-yl]ethanol

Under ice-cooling, 75 ml of diethylzinc and 33.5 g of diiodomethane wereadded to 500 ml of dichloroethane. After further adding a solution of6.53 g of2-[1-(benzyloxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]ethanol indichloroethane (20 ml), the resulting mixture was stirred at roomtemperature for 6 days. Then the reaction mixture was poured into amixture of saturated ammonium chloride with 1 N hydrochloric acid,washed with a saturated aqueous solution of sodium chloride and driedover anhydrous magnesium sulfate followed by filtration. Afterdistilling off the solvent under reduced pressure, the obtained residuewas purified by silica gel column chromatography (eluted withn-hexane/ethyl acetate) to thereby give 1.22 g of the title compound asan oily substance.

¹H-NMR(CDCl₃) δ ppm: 0.38-0.40(m, 1H), 0.50-0.54(m, 1H), 0.84-0.93(m,1H), 60-1.83(m, 2H), 2.05-2.16(m, 1H), 2.06-2.12(m, 1H), 3.23-3.28(m,1H), 3.57-3.62(m, 1H), 3.68-3.78(m, 3H), 3.98(s, 1H), 5.12(s, 1H),5.15(s, 1H), 7.28-7.40(m, 5H)

Example 3506-(tert-Butoxycarbonyl)-4,5,6,7-tetrahydro-6H-thieno[2,3-c]pyridine

The title compound was obtained as a yellow oily substance by the samemethod as the one described in Journal of Heterocyclic Chemistry, 27,1169 (1990).

¹H-NMR(CDCl₃) δ ppm: 1.49(s, 9H), 2.68-2.74(m, 2H), 3.65-3.71(m, 2H),4.63(br.s, 2H), 6.79(d, J=5.2 Hz, 1H), 7.14(d, J=5.2 Hz, 1H)

Example 351[6-(tert-Butoxycarbonyl)-4,5,6,7-tetrahydro-6H-thieno[2,3-c]pyridin-2-yl]carbaldehyde

To a solution of 0.63 g of diisopropylamine in 10 ml of tetrahydrofuranwas added 3.7 ml of a 1.6 M solution of n-butyllithium in hexane and theresulting mixture was stirred at 0° C. for 30 minutes. After cooling thereaction mixture to −70° C., a solution of 1.0 g of6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-6H-thieno[2,3-c]pyridine in10 ml of tetrahydrofuran was dropped thereinto followed by the additionof N,N,N,N-tetramethylethylenediamine. After stirring for 1 hour, 1.0 mlof N,N-dimethylformamide was added and stirring was continued foradditional 2 hours. After adding a saturated aqueous solution ofammonium chloride, the reaction mixture was extracted with ethylacetate. The organic layer was washed with water and a saturated aqueoussolution of sodium chloride and dried over anhydrous magnesium sulfate.After distilling off the solvent under reduced pressure, the residue waspurified by silica gel column chromatography (eluted with n-hexane/ethylacetate) to thereby give 0.35 g of the title compound as a yellow oilysubstance.

¹H-NMR(CDCl₃) δ ppm: 1.49(s, 9H), 2.73-2.79(m, 2H), 3.67-3.73(m, 2H),4.68(br.s, 2H), 7.48(s, 1H), 9.85(s, 1H)

Example 3522-[(1,3-Dithiacyclohexan-2-ylidene)methyl]-6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-6H-thieno[2,3-c]pyridine

The title compound was obtained as pale yellow crystals by the samemethod as the one of Production Example 62.

¹H-NMR(CDCl₃) δ ppm: 1.48(s, 9H), 2.21(quint, J=6.0 Hz, 2H),2.60-2.69(m, 2H), 2.98(t, J=6.0 Hz, 2H), 3.01(t, J=6.0 Hz, 2H),3.60-3.70(m, 2H), 4.59(br.s, 2H), 6.76(s, 1H), 6.93(s, 1H)

Example 353N-[8-Methyl-8-azabicyclo[3.2.1]oct-3-yl]-[7-(tert-butoxy-carbonyl)-7-azaspiro[3.5]non-2-yl]acetamide

1.7 g of [7-(tert-butoxycarbonyl)-7-azaspiro[3.5]non-2-yl]acetic acidwas dissolved in 50 ml of dichloromethane. After adding 0.9 ml oftriethylamine, the resulting mixture was ice-cooled. After adding 0.95ml of ethyl chloroformate, the resulting mixture was stirred at roomtemperature for 30 minutes. Then 1.9 g of3-amino-8-methyl-8-azabicyclo[3.2.1]octane dihydrochloride and 2.5 ml oftriethylamine were added thereto and the resulting mixture was stirredat room temperature for 6 hours. After adding water, the reactionmixture was extracted with ethyl acetate. The organic layer was washedwith 1 N sodium hydroxide and dried over anhydrous magnesium sulfate.After distilling off the solvent under reduced pressure, the obtainedcrystals were washed with ether to thereby give 1.25 g of the titlecompound as white crystals.

¹H-NMR(CDCl₃) δ ppm: 1.41-1.52(m, 4H), 1.45(s, 9H), 1.55-1.87(m, 4H),1.67-1.74(m, 2H), 2.02-2.10(m, 2H), 2.12-2.18(m, 2H), 2.18-2.25(m, 2H),2.27(d, J=9.0 Hz, 2H), 2.28(s, 3H), 2.56-2.68(m, 1H), 3.12-3.18(m, 2H),3.22-3.28(m, 2H), 3.31-3.36(m, 2H), 4.02-4.10(m, 1H), 5.75(br.d, J=9.0Hz, 1H)

Example 354 [2-(Benzyloxycarbonyl)-2-azaspiro[4.5]dec-8-yl]methanol

4.72 g of ethyl[4-(ethoxycarbonyl)-1-(nitromethyl)cyclohex-1-yl]acetatewas dissolved in 60 ml of ethanol. After adding 0.5 g of 10%palladium-carbon (moisture content: 50%) and 5.93 g of ammonium formate,the resulting mixture was heated to 60° C. for 1 hour. After allowing tocool, the reaction mixture was filtered and concentrated under reducedpressure. After adding tetrahydrofuran to the residue, the insolublematters were filtered off. After concentrating under reduced pressure,4.06 g a slightly pink oily substance was obtained.

This oily substance was heated to 180° C. for 2 hours and purified bysilica gel column chromatography (eluted with dichloromethane/methanol)to thereby give 2.19 g of a dark pinky red solid. This product wasdissolved in 10 ml of tetrahydrofuran and dropped under ice-cooling into40 ml of a suspension of 0.69 g of lithium aluminum hydride intetrahydrofuran. After stirring at room temperature for 30 minutes, thereaction mixture was heated under reflux for 4 hours. Then it wasice-cooled and 0.7 ml of water, 15% sodium hydroxide and 2.1 ml of waterwere successively added thereto. Further, celite was added thereto andthe resulting mixture was stirred at room temperature for 20 minutes.After filtration, it was concentrated under reduced pressure to therebygive 1.73 g of a slightly yellow oily substance.

This product was dissolved in 25 ml of methanol and 0.5 g of 10%palladium-carbon (moisture content: 50%) was added thereto. Theresulting mixture was stirred at room temperature under a hydrogenpressure of 1 atm for 4 hours and then heated to 60° C. for 3 hours and20 minutes. After allowing to cool, the reaction mixture was filteredand concentrated under reduced pressure to thereby give 1.48 g of acolorless oily substance.

This product was dissolved in 14 ml of tetrahydrofuran and added to 14ml of an aqueous solution of 0.666 g of anhydrous potassium carbonate.Then the mixture was cooled to −2° C. and 1.31 ml of benzylchloroformate was dropped thereinto while maintaining the bulktemperature at 0° C. or below. After the completion of the addition, theresulting mixture was stirred under ice-cooling for 45 minutes. Thenice-water was added to the reaction mixture followed by the extractionwith ethyl acetate. The organic layer was washed with water and asaturated aqueous solution of sodium chloride and dried over anhydroussodium sulfate. After concentrating under reduced pressure, the residuewas purified by silica gel column chromatography (eluted withdichloromethane/methanol) to thereby give 2.21 g of the title compoundas a colorless oily substance.

¹H-NMR(CDCl₃) δ ppm: 0.97-1.17(m, 2H), 1.28-1.78(m, 10H), 3.15-3.28(m,2H), 3.42-3.52(m, 4H), 5.12, 5.13(s, total 2H), 7.28-7.40(m, 5H)

Example 355Methyl[2-(benzyloxycarbonyl)-2-azaspiro[4.5]dec-8-yl]carboxylate

The following compound was obtained as a colorless oily substance by thesame method as those of Production Examples 73 and 74.

¹H-NMR(CDCl₃) δ ppm: 1.28-1.46(m, 2H), 1.55-1.92(m, 8H), 2.25-2.38(m,1H), 3.13-3.31(m, 2H), 3.42-3.51(m, 2H), 3.67, 3.68(s, total 3H), 5.12,5.13(s, total 2H), 7.29-7.39(m, 5H)

Example 356 2-Hydroxyphenyl(1-benzylpiperidin-4-yl)sulfamate

To a solution of 9.56 g of 1-benzyl-4-aminopiperidine inN,N-dimethylformamide (125 ml) was added 5.56 g of triethylamine at atemperature of 5° C. or lower. Next, a solution of 9.45 g of catecholsulfate [J. Org. Chem., 45 (26), 5371 (1980)] in dichloromethane (20 ml)was dropped thereinto and the resulting mixture was stirred for 2.5hours. The reaction mixture was poured into 500 ml of a 1% aqueoussolution of sodium chloride and extracted with diethyl ether thrice. Theorganic layer was washed with water 6 times, dried over anhydrousmagnesium sulfate and filtered. After distilling off the solvent underreduced pressure, the residue was purified by silica gel columnchromatography (eluted with dichloromethane/methanol) to thereby give19.08 g of the title compound as a colorless oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.58(dq, J=4, 12 Hz, 2H), 1.96(d, J=12 Hz, 2H),2.08(t, J=12 Hz, 2H), 2.81(m, 2H), 3.44(m, 1H), 3.48(s, 2H), 4.95(br.s,2H), 6.83(dt, J=2, 8 Hz, 1H), 6.91(dd, J=2, 8 Hz, 1H), 7.10(dt, J=2, 8Hz, 1H), 7.22(dd, J=2, 8 Hz, 1H), 7.24-7.32(m, 5H)

Example 357 N-(1-Benzylpiperidin-4-yl)-N,N′-pentamethylenesulfamide

To a solution of 1.81 g of2-hydroxyphenyl(1-benzylpiperidin-4-yl)sulfamate in 1,4-dioxane (25 ml)was added 0.47 g of piperidine and the resulting mixture was heatedunder reflux for 4 hours. Then the reaction mixture was poured into 100ml of water and extracted with ethyl acetate. The organic layer wasdried over anhydrous magnesium sulfate, filtered and distilled off underreduced pressure. The residue thus obtained was purified by silica gelcolumn chromatography (eluted with dichloromethane/methanol) to therebygive 0.701 g of the title compound as a colorless oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.48(m, 4H), 1.58-1.66(m, 4H), 1.96(d, J=12 Hz,2H), 2.10(t, J=12 Hz, 2H), 2.78(d, J=12 Hz, 2H), 3.14(t, J=5 Hz, 4H),3.21(m, 1H), 3.48(s, 2H), 3.94(d, J=7 Hz, 1H), 7.22-7.35(m, 5H)

Examples 358 to 361

The following compounds were obtained by the same method as the one ofExample 357.

Ex. Structural formula NMR 358

¹H-NMR(CDCl₃) δ ppm: 1.64(dq, J=2, 12Hz, 2H), 1.96(br.d, J=12Hz, 2H),2.09(t, J=12Hz, 2H), 2.80(br.d, J=12Hz, 2H), 3.17(t, J=5Hz, 4H), 3.25(m,1H), 3.48(s, 2H), 3.74(t, J=5Hz, 4H), 4.07(d, J=8Hz, 1H), 7.22- 7.35(m,5H) 359

¹H-NMR(CDCl₃) δ ppm: 1.25(t, J=7Hz, 3H), 1.52(dq, J=4, 11Hz, 2H),1.75(qd, J=3, 11Hz, 2H), 1.95(br.dt, J=3, 11Hz, 4H), 2.08(t, J=11Hz,2H), 2.38(tt, J=3, 11Hz, 1H), 2.76- 2.82(m, 4H), 3.20(m, 1H), 3.48(s,2H), 3.62(dt, J=3, 12Hz, 2H), 4.15(d, J=8Hz, 1H), 4.16(q, # J=7Hz, 2H),7.22-7.34(m, 5H) 360

¹H-NMR(CDCl₃) δ ppm: 1.53(dq, J=3, 12Hz, 2H), 1.97(br.d, J=12Hz, 2H),2.09(t, J=12Hz, 2H), 2.79(br.d, 12Hz, 2H), 3.27(m, 1H), 3.48(s, 2H),3.77(s, 3H), 3.82(s, 2H), 4.31(d, J=8Hz, 1H), 4.89(br.s, 1H), 7.20-7.33(m, 5H) 361

¹H-NMR(CDCl₃) δ ppm: 1.55(dq, J=3, 12Hz, 2H), 1.98(br.d, J=12Hz, 2H),2.09(br.t, J=12Hz, 2H), 2.81(br.d, J=12Hz, 2H), 3.19(br.s, 2H), 3.25(m,1H), 3.48(s, 2H), 3.75(t, J=5Hz, 2H), 4.46(br.s, 1H), 4.83(br.s, 1H),7.25-7.34(m, 5H)

Example 362

N-(Tetrazo-5-yl)-4-[1-(tert-butoxycarbonyl)piperidin-4-yl]-butanamide

Into 20 ml of a solution of 0.883 g of4-[1-(tert-butoxycarbonyl)piperidin-4-yl]butanoic acid intetrahydrofuran were successively added at 0° C. in a nitrogenatmosphere 0.67 g of triethylamine and 5 ml of a solution of 1.19 g ofdiethyl chlorophosphate in tetrahydrofuran and the resulting mixture wasthen stirred at 0° C. for 2 hours. To this reaction mixture were added0.527 g of 5-aminotetrazole and 10 ml of a solution of 0.54 g oftriethylamine in tetrahydrofuran and the resulting mixture was stirredfor additional 15 hours. After distilling off the solvent under reducedpressure, ethyl acetate and water were added to the residue and the pHvalue thereof was adjusted to 4 with formic acid. Then the aqueous layerwas extracted with ethyl acetate. The organic layers were combined,dried over anhydrous magnesium sulfate and filtered. After concentratingunder reduced pressure, the residue was purified by silica gel columnchromatography (eluted with dichloromethane/methanol) to thereby give0.875 g of the title compound as white crystals.

¹H-NMR(CDCl₃) δ ppm: 1.10(dq, J=5, 12 Hz, 2H), 1.38(m, 3H), 1.45(s, 9H),1.68(m, 2H), 1.85(m, 2H), 2.67(m, 2H), 2.71(t, J=6 Hz, 2H), 4.08(m, 2H),12.45(s, 1H)

Example 363Methyl[3-(benzyloxycarbonyl)-3-azabicyclo[4.1.0]hept-6-yl]-acetate

1.41 g of oxalyl chloride was dissolved in 70 ml of dichloromethane andcooled to −78° C. in a nitrogen atmosphere. Into the solution wasdropped a solution of 1.38 g of dimethyl sulfoxide in dichloromethane (3ml) over 5 minutes. Further, a solution of 1.22 g of2-[3-(benzyloxycarbonyl)-3-azabicyclo[4.1.0]hept-6-yl]ethanol indichloromethane (10 ml) was dropped thereinto over 5 minutes. Afterstirring for 15 minutes, 2.24 g of triethylamine was dropped thereintoover 5 minutes and stirring was continued for additional 30 minutes.Then the reaction mixture was diluted with dichloromethane, washed with1 N hydrochloric acid and a saturated aqueous solution of sodiumchloride and dried over anhydrous magnesium sulfate followed byfiltration. After distilling off the solvent under reduced pressure, theobtained residue was purified by silica gel column chromatography(eluted with n-hexane/ethyl acetate) to thereby give 450 mg of aproduct. Next, this compound was dissolved in 6 ml of dimethyl sulfoxideand 5 ml of an aqueous solution of 257 mg of sodium dihydrogenphosphatewas added thereto. After adding 5 ml of an aqueous solution of 496 mg ofsodium chlorite over 5 minutes, the resulting mixture was stirred atroom temperature for 10 minutes. Then the reaction mixture was dilutedwith ethyl acetate, washed successively with water and a saturatedaqueous solution of sodium chloride, dried over anhydrous magnesiumsulfate and filtered. After distilling off the solvent under reducedpressure, the obtained residue was dissolved in 40 ml of toluene. Afteradding 6 ml of a 2 M solution of trimethylsilyldiazomethane in hexaneand 10 ml of methanol, the resulting mixture was stirred at roomtemperature for 50 minutes. After concentrating the reaction mixtureunder reduced pressure, the obtained residue was purified by silica gelcolumn chromatography (eluted with n-hexane/ethyl acetate) to therebygive 180 mg of the title compound as an oily substance.

¹H-NMR(CDCl₃) δ ppm: 0.41-0.48(m, 1H), 0.54-0.66(m, 1H), 0.88-1.04(m,1H), 1.76-1.92(m, 2H), 2.16-2.42(m, 2H), 3.15-3.24(m, 1H), 3.32-3.44(m,1H), 3.60-3.68(m, 1H), 3.68(s, 3H), 3.80-3.88(m, 1H), 5.12(s, 2H),7.28-7.40(m, 5H)

Examples 364 to 386

Starting with known compounds, the following compounds were obtained bythe same method as the one of Example 63.

Ex. Structural formula NMR 364

¹H-NMR(CDCl₃) δ ppm: 1.34-1.48(br · s, 2H), 1.54-1.62(m, 4H), 2.30-2.45(br · s, 4H), 3.41(s, 2H), 3.54(s, 3H), 5.26(s, 2H), 6.92(s, 2H),7.12(s, 1H), 7.80(s, 2H) 365

¹H-NMR(CDCl₃) δ ppm: 1.23(t, J=6Hz, 3H), 1.60- 1.80(m, 2H), 1.82-1.90(m,2H), 1.92-2.08(m, 2H), 2.20-2.32(m, 1H), 2.75- 2.85(m, 2H), 3.41(s, 2H),3.52(s, 3H), 4.12(q, J=6Hz, 2H), 5.26(s, 2H), 6.92(d, J=8Hz, 1H),6.94(d, J=8Hz, 1H), 7.10(s, 1H), 7.82(s, 2H) 366

¹H-NMR(CDCl₃) δ ppm: 1.50-1.62(m, 2H), 1.80- 1.90(m, 2H), 2.05-2.16(m,2H), 2.10-2.30(br · s, 1H), 2.68-2.80(m, 2H), 3.40(s, 2H), 3.52(s, 3H),3.60- 3.70(m, 1H), 5.26(s, 2H), 6.88(d, J=8Hz, 1H), 6.92(d, J=8Hz, 1H),7.08(s, 1H), 7.80(s, 2H) 367

¹H-NMR(CDCl₃) δ ppm: 1.50-1.62(m, 2H), 1.82- 1.92(m, 2H), 2.06- 2.17(m,2H), 2.64- 2.74(m, 2H), 3.16- 3.24(m, 1H), 3.34(s, 3H), 3.42(s, 2H),3.54(s, 3H), 5.26(s, 2H), 6.92(d, J=8Hz, 1H), 6.94(d, J=8Hz, 1H),7.10(s, 1H), 7.82(s, 2H) 368

¹H-NMR(CDCl₃) δ ppm: 1.22(s, 3H), 1.23(s, 1H), 1.50-1.60(m, 2H), 1.60-1.70(m, 2H), 2.45- 2.55(m, 2H), 2.32- 2.43(m, 2H), 3.43(s, 2H), 3.54(s,3H), 5.26(s, 2H), 6.94(s, 2H), 7.09(s, 1H), 7.80(s, 2H) 369

¹H-NMR(CDCl₃) δ ppm: 1.68-1.82(m, 2H), 1.82- 1.89(m, 2H), 1.90- 2.30(m,2H), 2.08- 2.20(m, 1H), 2.86- 2.95(m, 2H), 3.42(s, 2H), 3.54(s, 3H),5.26(s, 2H), 5.50- 5.62(br · s, 2H), 6.92(d, J=8Hz, 1H), 6.95(d, J=8Hz,1H), 7.09(s, 1H), 7.80(s, 2H) 370

¹H-NMR(CDCl₃) δ ppm: 1.69-1.80(m, 2H), 1.80- 1.90(m, 2H), 2.02(t, J=6Hz,2H), 2.38-2.50(m, 2H), 2.52-2.62(m, 2H), 2.57(t, J=6Hz, 2H), 3.43(s,2H), 3.52(s, 3H), 5.26(s, 2H), 6.92(d, J=8Hz, 1H), 6.94(d, J=8Hz, 1H),7.08(s, 1H), 7.80(s, 2H) 371

¹H-NMR(CDCl₃) δ ppm: 1.50-1.68(m, 2H), 1.68- 1.80(m, 1H), 1.78-1.90(m,1H), 2.10-2.30(m, 1H), 2.30-2.42(m, 1H), 2.42- 2.50(m, 1H), 2.58-2.70(m,1H), 2.70-2.80(br · s, 1H), 3.35(d, J=13Hz, 1H), 3.41(d, J=13Hz, 1H),3.49(s, 3H), 5.26(s, 2H), 5.80(br · s, 2H), # 6.82(d, J=8Hz, 1H),6.93(d, J=8Hz, 1H), 7.06(s, 1H), 7.80(s, 2H) 372

¹H-NMR(CDCl₃) δ ppm: 1.20-1.40(m, 2H), 1.50- 1.70(m, 2H), 1.70-1.80(m,1H), 1.97-2.08(m, 2H), 2.80-2.92(m, 1H), 2.92- 2.97(m, 1H), 3.22(d,J=14Hz, 1H), 3.52(s, 3H), 3.82(d, J=14Hz, 1H), 5.26(s, 2H), 6.60-6.70(br · s, 2H), 6.92(d, J=8Hz, 1H), 6.97(d, J=8Hz, 1H), # 7.11(s, 1H),7.82(d, J=3Hz, 1H) 373

¹H-NMR(CDCl₃) δ ppm: 1.70-1.82(m, 2H), 1.82- 2.00(m, 1H), 2.15- 2.30(m,1H), 2.30- 2.40(m, 1H), 3.00- 3.10(m, 1H), 3.10- 3.20(m, 1H), 3.42(d,J=14Hz, 1H), 3.50(s, 3H), 3.82(d, J=14Hz, 1H), 5.26(s, 2H), 5.95-6.15(br · s, 1H), 6.89(d, J=8Hz, 1H), 6.94(d, J= # 8Hz, 1H), 7.08(s,1H), 7.10-7.20(br · s, 1H), 7.80(s, 2H) 374

¹H-NMR(CDCl₃) δ ppm: 1.20-1.36(m, 2H), 1.35- 1.45(m, 1H), 1.45- 1.55(m,2H), 1.60- 1.70(m, 2H), 1.90- 2.00(m, 2H), 2.70- 2.80(br · s, 1H), 2.80-2.90(m, 2H), 3.42(s, 2H), 3.54(s, 3H), 3.66(t, J=6Hz, 2H), 5.25(s, 2H),6.92(s, 2H), 7.08(s, 1H), 7.81(s, 2H) 375

¹H-NMR(CDCl₃) δ ppm: 1.02(d, J=7Hz, 3H), 1.04(d, J=7Hz, 3H),1.20-1.40(m, 2H), 1.50- 1.70(m, 4H), 2.40- 2.50(m, 2H), 3.53(s, 3H),3.72(s, 2H), 5.24(s, 2H), 6.92(d, J=8Hz, 1H), 6.97(d, J=8Hz, 1H),7.24(s, 1H), 7.82(s, 2H) 376

¹H-NMR(CDCl₃) δ ppm: 1.62-1.76(m, 2H), 1.86- 1.96(m, 2H), 2.18- 2.30(m,2H), 2.64- 2.74(m, 2H), 3.42(s, 2H), 3.54(s, 3H), 4.50- 4.70(m, 3H),5.32(s, 2H), 6.92(d, J=8Hz, 1H), 6.94(d, J=8Hz, 1H), 7.12(s, 1H),7.82(s, 2H) 377

¹H-NMR(CDCl₃) δ ppm: 1.16-1.30(m, 4H), 1.30- 1.40(m, 2H), 1.50- 1.60(m,2H), 1.60- 1.70(m, 2H), 1.70- 1.90(m, 2H), 1.94(m, 2H), 2.82-2.90(m,2H), 3.44(s, 2H), 3.54(s, 3H), 3.62(t, J=6Hz, 2H) 5.28(s, 2H), 6.92(d,J=8Hz, 1H), 6.94(d, J=8Hz, 1H), 7.09(s, 1H), 7.82(s, 2H) 378

¹H-NMR(CDCl₃) δ ppm: 3.49(s, 3H), 5.06(s, 2H), 5.22(s, 2H), 6.16(dt,J=2, 7Hz, 1H), 6.62(ddd, J=1, 2, 9Hz, 1H), 6.87(dd, J=2, 8Hz, 1H),6.97(d, J=8Hz, 1H), 7.08(d, J=2Hz, 1H), 7.28(ddd, J=1, 2, 7Hz, 1H),7.34(ddd, J=2, 7, 9Hz, 1H), 7.83(d, J=3Hz, 1H), 7.84(d, J=3Hz, 1H) 379

¹H-NMR(CDCl₃) δ ppm: 3.48(s, 3H), 4.88(s, 2H), 5.22(s, 2H), 6.45(d,J=8Hz, 2H), 6.75(dd, J=1, 8Hz, 1H), 6.91(d, J=2Hz, 1H), 7.03(d, J=8Hz,1H), 7.33(d, J=8Hz, 2H), 7.85(d, J=3Hz, 1H), 7.87(d, J=3Hz, 1H) 380

¹H-NMR(CDCl₃) δ ppm: 1.44(m, 2H), 1.60(m, 4H), 2.41(br · s, 4H), 3.46(s,2H), 3.53(s, 3H), 5.03(s, 2H), 6.87(d, J=6Hz, 1H), 6.93(d, J=8Hz, 1H),7.03(d, J=8Hz, 1H), 7.07(s, 1H), 8.17(s, 1H), 8.25(d, J=6Hz, 1H) 381

¹H-NMR(CDCl₃) δ ppm: 1.81-1.98(m, 4H), 2.26- 2.38(m, 2H), 2.60- 2.69(m,3H), 3.43(s, 2H), 3.54(s, 3H), 5.27(s, 2H), 6.91(dd, J=1.5, 7.7Hz, 1H),6.96(d, J=7.7Hz, 1H), 7.09(d, J=1.5Hz, 1H), 7.83(d, J=2.7Hz, 1H),7.84(d, J=2.7Hz, 1H) 382

¹H-NMR(CDCl₃) δ ppm: 2.55(br · t, J=4.8Hz, 4H), 2.78(s, 3H), 3.23(br ·t, J=4.8Hz, 4H), 3.47(s, 2H), 3.53(s, 3H), 5.28(s, 2H), 6.92(dd, J=1.5,7.9Hz, 1H), 6.96(d, J=7.9Hz, 1H), 7.09(d, J=1.5Hz, 1H), 7.82(d, J=2.8Hz,1H), 7.83(d, J=2.8Hz, 1H) 383

¹H-NMR(CDCl₃) δ ppm: 1.96-2.23(m, 2H), 2.28(s, 3H), 2.30-2.65(m, 6H),3.43(s, 2H), 3.53(s, 3H), 5.23(s, 2H), 6.93(dd, J=1.4, 8.3Hz, 1H),6.95(d, J=8.3Hz, 1H), 7.10(d, J=1.4Hz, 1H), 7.82(d, J=2.8Hz, 1H),7.83(d, J=2.8Hz, 1H) 384

¹H-NMR(CDCl₃) δ ppm: 2.38-2.50(m, 4H), 3.43(s, 2H), 3.53(s, 3H), 3.68-3.75(m, 4H), 5.28(s, 2H), 6.94(dd, J=1.1, 8.0Hz, 1H), 6.96(d, J=8.0Hz,1H), 7.12(d, J=1.1Hz, 1H), 7.83(d, J=2.8Hz, 1H), 7.84(d, J=2.8Hz, 1H),385

¹H-NMR(CDCl₃) δ ppm: 1.7-1.96(m, 4H), 1.96(m, 2H), 2.1-2.24(m, 1H),2.93(br · d, J=12Hz, 2H), 3.38(s, 2H), 3.47(s, 3H), 5.32(s, 2H), 5.50(br· s, 1H), 5.60(br · s, 1H), 6.77(s, 2H), 6.89(s, 1H), 7.42(d, J=3Hz,1H), 7.57(d, J=3Hz, 1H) 386

¹H-NMR(CDCl₃) δ ppm: 1.29-1.40(m, 2H), 1.63- 1.73(m, 2H), 1.75(s, 3H),1.92-2.01(m, 2H), 2.68- 2.76(m, 2H), 3.37(s, 2H), 3.38(s, 3H),3.41-3.54(m, 1H), 5.23(s, 2H), 6.92(dd, J=1.2, 7.9Hz, 1H), 7.05(d,J=7.9Hz, 1H), 7.09(d, J=1.2Hz, 1H), 7.75(br · d, J=7.5Hz, 1H), # 7.92(d,J=2.7Hz, 1H), 7.95(d, J=2.7Hz, 1H)

Examples 387 to 392

The following compounds were obtained by the same method as the one ofExample 64 by using anhydrous potassium carbonate, sodiumhydrogencarbonate or pyridine as a substitute forN,N-diisopropylethylamine.

Ex. Structural formula NMR 387

¹H-NMR(CDCl₃) δ ppm: 1.57(m, 2H), 1.99(m, 4H), 2.21(m, 2H), 2.78(s, 6H),3.24(m, 1H), 3.37(s, 3H), 3.44(s, 2H), 3.96(d, J=4Hz, 1H), 5.24(s, 2H),7.03(dd, J=2, 8Hz, 1H), 7.10(d, J=8Hz, 1H), 7.11 (d, J=2Hz, 1H), 7.22(d,J=5Hz, 1H), 8.16(d, J=5Hz, 1H) 388

¹H-NMR(CDCl₃) δ ppm: 1.5-1.65(m, 2H), 1.9- 2.05(m, 2H), 2.13(t, J=7Hz,2H), 2.75-2.85(m, 2H), 2.99(s, 3H), 3.30- 3.40(m, 1H), 3.44(s, 2H),3.53(s, 3H), 4.20- 4.35(m, 1H), 5.30(s, 2H), 6.93(d, J=8Hz, 1H), 6.97(d,J=8Hz, 1H), 7.10(s, 1H), 7.82- 7.87(m, 2H) 389

¹H-NMR(CDCl₃) δ ppm: 1.2-1.4(m, 3H), 1.4- 1.5(m, 2H), 1.5-1.8(m, 2H),1.96(s, 3H), 1.9- 2.1(m, 2H), 2.8-2.95(m, 2H), 3.22-3.3(m, 2H),3.4-3.46(m, 2H), 3.53(s, 3H), 5.28(s, 2H), 5.3- 5.4(m, 1H), 6.7-6.96(m,1H), 6.96(d, J=8Hz, 1H), 7.08-7.12(m, 1H), 7.8- 7.86(m, 2H) 390

¹H-NMR(CDCl₃) δ ppm: 1.2-1.4(m, 3H), 1.44- 1.54(m, 2H), 1.56- 1.68(m,2H), 1.86- 2.00(m, 2H), 2.8-2.9(m, 2H), 2.94(s, 3H), 3.08- 3.20(m, 2H),3.42(s, 2H), 3.53(s, 3H), 4.35(br.s, 1H), 5.28(s, 2H), 6.91(d, J=8Hz,1H), 6.95(d, J=8Hz, 1H), 7.08(s, 1H), 7.76- 7.86(m, 2H) 391

¹H-NMR(CDCl₃) δ ppm: 1.50-1.70(m, 2H), 1.90- 2.05(m, 2H), 2.05- 2.17(m,2H), 2.71(d, J=6Hz, 3H), 2.73-2.84(m, 2H), 3.17-3.30(m, 1H), 3.42(s,2H), 3.53(s, 3H), 4.00-4.15(m, 2H), 5.28(s, 2H), 6.91(dd, J=1, 8Hz, 1H),6.96(d, J=8Hz, 1H), 7.09(d, J=1Hz, 1H), 7.83(d, # J=2Hz, 1H), 7.84(d,J=2Hz, 1H) 392

¹H-NMR(CDCl₃) δ ppm: 1.5-1.63(m, 2H), 1.97- 2.08(m, 2H), 2.05- 2.18(m,2H), 2.73- 2.85(m, 2H), 3.28- 3.40(m, 1H), 3.42(s, 2H), 3.54(s, 3H),4.34(d, J=10Hz, 1H), 4.6(br.s, 2H), 5.29(s, 2H), 6.91(dd, J=1, 8Hz, 1H),6.96(d, J=8Hz, 1H), 7.08(d, J=1Hz, 1H), # 7.83(d, J=2Hz, 1H),7.84(J=2Hz, 1H)

Example 393N,N-[3-[10-(Methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzo-thiazin-8-ylmethyl]amiono]pentamethylene]methanesulfonamide

The title compound was obtained by the same method as the one of Example66.

¹H-NMR(CDCl₃) δ ppm: 1.5-1.65(m, 2H), 1.95-2.05(m, 2H), 2.6-2.7(m, 1H),2.77(s, 3H), 2.7-2.85(m, 2H), 3.53(s, 3H), 3.6-3.8(m, 2H), 3.77(s, 2H),5.30(s, 3H), 6.92-7.0(m, 2H), 7.14(s, 1H), 7.83(d, J=3 Hz, 1H), 7.84(d,J=3 Hz, 1H)

Example 394[1-[10-(Methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-2,3-dehydro-4-piperidone

Into a solution of 0.130 g of sodium aluminum hydride in tetrahydrofuran(10 ml) was dropped in a nitrogen atmosphere a solution of 0.858 g of[1-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-4-pyridonein tetrahydrofuran (20 ml). After reacting for 16 hours, 0.13 ml ofwater, 0.13 ml of a 15% aqueous solution of sodium hydroxide and 0.40 mlof water were successively added thereto and the insoluble matters werefiltered off. After distilling off the solvent under reduced pressure,the residue was purified by silica gel column chromatography (elutedwith dichloromethane/methanol) to thereby give 0.277 g of the titlecompound as pale yellow crystals.

¹H-NMR(CDCl₃) δ ppm: 2.48(t, J=8 Hz, 2H), 3.38(t, J=8 Hz, 2H), 3.53(s,3H), 4.29(s, 2H), 5.04(d, J=8 Hz, 1H), 5.26(s, 2H), 6.68(dd, J=2, 8 Hz,1H), 7.03(d, J=8 Hz, 1H), 7.05(d, J=2 Hz, 1H), 7.14(d, J=8 Hz, 1H),7.85(d, J=3 Hz, 1H), 7.87(d, J=3 Hz, 1H)

Example 395[1-[10-(Methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-3-phthalimidomethylpyridiniumchloride

0.587 g of8-chloromethyl-10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazineand a solution of 0.524 g of N-(3-pyridylmethyl)phthalimide in 10 ml ofdimethylforamide were heated to 80° C. in a nitrogen atmosphere for 4hours. After distilling off the solvent under reduced pressure, theresidue was purified by silica gel column chromatography (eluted withdichloromethane/methanol) to thereby give 0.489 g of the title compoundas yellow crystals.

¹H-NMR(CDCl₃) δ ppm: 3.53(s, 3H), 5.04(s, 2H), 5.32(s, 2H), 6.22(s, 2H),7.02(d, J=8 Hz, 1H), 7.22(dd, J=2, 8 Hz, 1H), 7.40(d, J=2 Hz, 1H),7.76(dd, J=3, 6 Hz, 2H), 7.84-7.87(m, 5H), 8.01(dd, J=6, 8 Hz, 1H),8.30(dd, J=1, 6 Hz, 1H), 9.26(d, J=lHz, 1H)

Example 3962-[1-(10-(Methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-3,4-dehydropiperidin-3-ylmethyl]-3-hydroxyiso-indolin-1-one

To a solution of 0.486 g of[1-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-3-phthalimidomethylpyridiniumchloride in methanol (10 ml) was added 0.086 g of sodium borohydride andthe resulting mixture was stirred for 30 minutes. Next, 20 ml oftetrahydrofuran and 10 ml of water were further added and the mixturewas stirred for additional 1 hour. After neutralizing with sodiumdihydrogenphosphate, the mixture was extracted with dichloromethane (50ml) and the organic layer was dried over anhydrous magnesium sulfate.After filtering and distilling off the solvent under reduced pressure,0.255 g of the title compound was obtained as pale yellow crystals.

¹H-NMR(CDCl₃) δ ppm: 2.16(br.s, 2H), 2.42(quint, J=6 Hz, 1H),2.51-2.56(quint, J=6 Hz, 1H), 2.54(d, J=15 Hz, 1H), 2.98(d, J=15 Hz,1H), 3.44(d, J=12 Hz, 1H), 3.46(s, 3H), 3.50(d, J=12 Hz, 1H), 3.94(d,J=15 Hz, 1H), 4.20(d, J=15 Hz, 1H), 5.22(d, J=10 Hz, 1H), 5.25(d, J=10Hz, 1H)5.74(br.s, 1H), 5.78(s, 1H), 6.88(dd, J=1, 8 Hz, 1H), 6.91(d, J=8Hz, 1H), 7.05(d, J=1 Hz, 1H), 7.48(dt, J=1, 7 Hz, 1H), 7.56(dd, J=1, 7Hz, 1H), 7.59(dd, J=1, 7 Hz, 1H), 7.76(dt, J=1, 7 Hz, 1H), 7.81(d, J=3Hz, 1H), 7.83(d, J=3 Hz, 1H)

Example 397N-[1-[10-(Methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-3,4-dehydropiperidin-3-ylmethyl]-2-hydroxymethyl-benzamide

To a solution of 0.255 g of2-[1-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-3,4-dehydropiperidin-3-ylmethyl]-3-hydroxyisoindolin-1-onein 2-propanol (7.7 ml) were added 1.3 ml of water and 0.163 g of sodiumborohydride and the resulting mixture was stirred for 16 hours. Then thereaction mixture was naturalized with sodium dihydrogenphosphate andextracted with ethyl acetate. The organic layer was dried over anhydrousmagnesium sulfate and filtered. After distilling off the solvent underreduced pressure, 0.235 g of the title compound was obtained as paleyellow crystals.

¹H-NMR(CDCl₃) δ ppm: 2.21(br.s, 1H), 2.58(t, J=6 Hz, 2H), 2.99(br.s,2H), 3.48(s, 3H), 3.51(s, 3H), 3.99(d, J=5 Hz, 2H), 4.51(s, 2H), 5.26(s,2H), 5.76(s, 1H), 6.68(br.s, 1H), 6.91(s, 2H), 7.11(s, 1H), 7.32-7.44(m,3H), 7.52(d, J=8 Hz, 1H), 7.82(d, J=3 Hz, 1H), 7.84(d, J=3 Hz, 1H)

Example 398[1-[10-(Methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-3-aminomethyl-3,4-dehydropiperidine

To a solution of 0.235 g ofN-[1-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-3,4-dehydropiperidin-3-ylmethyl]-2-hydroxymethylbenzamidein 2-propanol (8 ml) were added 1.5 ml of water and 0.9 ml of aceticacid and the resulting mixture was stirred at 80° C. for 2 hours. Afterdistilling off the solvent under reduced pressure, the residue waspurified by silica gel column chromatography (eluted withdichloromethane/methanol) to thereby give 0.120 g of the title compoundas a pale yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 2.16(br.s, 2H), 2.52(t, J=6 Hz, 2H), 2.94(br.s,2H), 3.17(s, 2H), 3.53(s, 3H), 3.55(s, 2H), 5.29(s, 2H), 5.63(m, 1H),6.96(d, J=8 Hz, 1H), 6.99(dd, J=2, 8 Hz, 1H), 7.11(d, J=2 Hz, 1H),7.83(d, J=3 Hz, 1H), 7.84(d, J=3 Hz, 1H)

Example 399N-[1-[10-(Methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-3,4-dehydropiperidin-3-ylmethyl]methanesulfonamide

The title compound was obtained as pale yellow crystals by the samemethod as the one of Example 316.

¹H-NMR(CDCl₃) δ ppm: 2.38(m, 2H), 2.84(m, 2H), 2.96(s, 3H), 3.38(br.s,2H), 3.54(s, 3H), 3.68(d, J=5 Hz, 2H), 3.88(br.s, 2H), 5.33(s, 2H),5.49(br.s, 1H), 5.86(m, 1H), 7.00(d, J=8 Hz, 1H), 7.06(br.d, J=8 Hz,1H), 7.26(br.s, 1H), 7.83(d, J=3 Hz, 1H), 7.84(d, J=3 Hz, 1H)

Example 400 EthylN-[1-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-2,3-dehydro-3-piperidinecarboxylate

To a solution of 0.506 g of diisopropylamine in tetrahydrofuran (16 ml)was added at 0° C. in a nitrogen atmosphere a 1.6 M solution ofn-butyllithium in hexane. Further a solution of 0.776 g of ethyl2,3-dehydro-3-piperidinecarboxylate in tetrahydrofuran (2 ml) was addedthereto. In another container, 1.00 g of8-chloromethyl-10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazinewas added at 60° C. in a nitrogen atmosphere to a solution of 1.53 g ofsodium iodide in N,N-dimethylformamide (10 ml). After heating for 2hours, the mixture was brought back to room temperature and then addedto the above-mentioned solution of the lithium salt. After stirring atroom temperature for 2 hours and concentrating under reduced pressure,the residue was distributed into ethyl acetate and water. The organiclayer was concentrated and the residue was purified by silica gel columnchromatography (eluted with dichloromethane/methanol) to thereby give0.375 g of the title compound as pale yellow crystals.

¹H-NMR(CDCl₃) δ ppm: 1.26(t, J=7 Hz, 3H), 1.52(quint, J=6 Hz, 2H),2.29(t, J=6 Hz, 2H), 2.98(t, J=6 Hz, 2H), 3.49(s, 3H), 4.15(q, J=7 Hz,2H), 4.23(s, 2H), 5.22(s, 2H), 6.82(dd, J=2, 7 Hz, 1H), 6.97(d, J=2 Hz,1H), 6.98(d, J=7 Hz, 1H), 7.51(s, 1H), 7.83(d, J=3 Hz, 1H), 7.84(d, J=3Hz, 1H)

Example 401

The following compounds were obtained by the same method as the one ofExample 8.

Ex. Structural formula MS M.p. NMR 401

ESI (+) 420 (MH⁺) 168-170° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.0-1.2(m, 2H),1.24- 1.40(m, 3H), 1.54-1.66(m, 2H), 1.74-1.90(m, 2H), 2.65-2.80(m, 2H),2.85(s, 3H), 2.92(q, J=7Hz, 2H), 3.23(br · s, 2H), 6.65- 6.75(m, 1H),6.74(s, 1H), 6.82(d, J=8Hz, 1H), 6.89(t, J=6Hz, # 1H), 7.62(d, J=3Hz,1H), 7.63(d, J=3Hz, 1H), 9.43(m, 1H) 402

ESI (+) 392 (MH⁺) 220-223° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.3-1.5(m, 2H),1.70- 1.80(m, 2H), 1.85-2.00(m, 2H), 2.60-2.75(m, 2H), 2.88(s, 3H),3.00-3.20(m, 1H), 3.23(s, 2H), 6.63- 6.70(m, 1H), 6.73(s, 1H), 6.82(d,J=8Hz, 1H), 7.0- 7.1(m, 1H), 7.62(d, J=3Hz, 1H), # 7.63(d, J=3Hz, 1H),9.44(s, 1H) 403

ESI (+) 407 (MH⁺) 209-210° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.34-1.48(m, 2H),1.72- 1.80(m, 2H), 1.82-1.94(m, 2H), 2.41(d, J=4Hz, 3H), 2.64-2.74(m,2H), 2.84- 2.96(m, 1H), 3.22(s, 2H), 6.55-6.63(m, 1H), 6.67(d, J=8Hz,1H), 6.73(s, 1H), 6.82(d, J=8Hz, 1H), 6.87 # (d, J=8Hz, 1H), 7.62(d,J=3Hz, 1H), 7.62(d, J=3Hz, 1H), 9.44(s, 1H) 404

ESI (+) 393 (MH⁺) 196-199° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.32-1.48(m, 2H),1.74- 1.88(m, 2H), 1.82-1.98(m, 2H), 2.6-2.76(m, 2H), 2.94-3.1(m, 1H),3.22(s, 2H), 6.45(s, 2H), 6.53(d, J=7Hz, 1H), 6.67(d, J=8Hz, 1H),6.73(d, J=1Hz, 1H), 6.82(d, J=8Hz, 1H), # 7.61(d, J=3Hz, 1H), 7.63(d,J=3Hz, 1H), 9.44(s, 1H) 405

ESI (+) 384 (MH⁺) 194-196° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.0-1.36(m, 5H),1.5- 1.66(m, 2H), 1.75(s, 3H), 1.7-1.9(m, 2H), 2.64- 2.80(m, 2H),2.94-3.06(m, 2H), 3.21(m, 2H), 6.6- 6.75(m, 1H), 6.73(m, 1H),6.7-6.88(m, 1H), 7.62(br · s, 2H), 7.75(br · s, 1H), 9.43(m, 1H) 406

FAB (+) 392 (MH⁺) 219-221° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.24-1.38(m, 2H),1.80- 1.90(m, 2H), 2.06-2.20(m, 1H), 2.75(t, J=7.2Hz, 2H), 2.81(s, 3H),3.38- 3.48(m, 2H), 3.54(s, 2H), 6.75(d, J=8.0Hz, 1H), 6.77(s, 1H),6.81(d, J=8.0Hz, 1H), 7.61(d, J=2.8Hz, 1H), # 7.62(d, J=8.2Hz, 1H),9.45(s, 1H), 407

ESI (+) 454 (MH⁺) 157-158° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.25-1.40(m, 2H),1.40- 1.55(m, 2H), 1.70-1.90(m, 2H), 2.50-2.65(m, 2H), 2.85-2.95(m, 1H),3.17(s, 2H), 6.60-6.68(m, 1H), 6.68(s, 1H), 6.80(br · d, J=8Hz, 1H),7.50-7.65(m, 5H), 7.68-7.75(m, 1H), 7.75- # 7.82(m, 2H), 9.41(s, 1H) 408

FAB (+) 404 (MH⁺) 110-112° C. ¹H-NMR(DMSO-d₆) δ ppm: 2.07(br · s, 2H),2.42(t, J=3Hz, 2H), 2.79(br · s, 2H), 2.83(s, 3H), 3.36(s, 2H), 3.43(br· d, J=3Hz, 2H), 5.74(br · s, 1H), 6.71(dd, J=1, 8Hz, 1H), 6.77(d,J=1Hz, 1H), 6.84(d, J=8Hz, 1H), 7.24 #(t, J=3Hz, 1H), 7.63(s, 2H),9.44(s, 1H) 409

FAB (+) 358 (MH⁺) 139-142° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.44(m, 2H),1.70-1.85(m, 2H), 2.50-2.70(m, 2H), 3.15(d, J=10Hz, 1H), 3.20-3.40(m,2H), 3.25(d, J=10Hz, 1H), 4.30- 4.50(br · s, 3H), 6.68(d, J=8Hz, 1H),6.71(s, 1H), 6.85(d, J=8Hz, 1H), 7.62(s, 2H), 9.45(br · s, 1H) 410

FAB (+) 371 (MH⁺) 132-135° C. ¹H-NMR(DMSO-d₆) δ ppm: 0.95-1.30(m, 7H),1.30-1.40(m, 2H), 1.50-1.62(m, 2H), 1.70-1.90(m, 2H), 2.70-2.80(m, 2H),3.21(s, 2H), 3.30- 3.40(m, 2H), 4.31(t, J=5Hz, 1H), 6.65(d, J=8Hz, 1H),6.74(s, 1H), 6.81(d, J=8Hz, 1H), # 7.61(s, 2H), 9.42(br · s, 1H) 411

FAB (+) 308 (MH⁺) 168° C. (decompose) ¹H-NMR(DMSO-d₆) δ ppm: 4.95(s,2H), 6.09- 6.15(m, 2H), 6.46(d, J=1.5Hz, 1H), 6.52(d, J=5.5Hz, 1H),6.75(dd, J=1.5, 7.9Hz, 1H), 6.96(d, J=7.9Hz, 1H), 7.66-7.72(m, 2H),7.88(s, 1H), 7.97(d, J=5.5Hz, 1H), 9.20(s, 1H)

Examples 412 to 433

The following compounds were obtained by the same method as that ofExample 9.

Ex. Structural formula MS M.p. NMR 412

FAB (+) 356 (MH⁺) 212- 214° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.25-1.40 (m,2H), 1.60-1.72 (m, 2H), 1.87-2.02 (m, 2H), 2.48 (s, 3H), 2.60-2.78 (m,2H), 3.23 (s, 2H), 3.40-3.54 (m, 1H), 6.68 (d, J = 8.3 Hz, 1H), 6.73 (s,1H), 6.83 (d, J = 8.3 Hz, 1H), 7.62 (s, 2H), 7.73 (d, J = 7.6 Hz, 1H),9.44 (s, 1H) 413

ESI (+) 326 (MH⁺) 287- 288° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.40-1.58 (m,2H), 1.58-1.68 (m, 2H), 1.84 (br.t, J = 11 Hz, 2H), 1.96-2.08 (m, 1H),2.76 (br.d, J = 11 Hz, 2H), 3.22 (s, 2H), 6.57 (d, J = 8 Hz, 1H), 6.60(s, 1H), 6.68 (d, J = 8 Hz, 1H), 6.66-6.74 (m, 1H), 7.19 (br.s, 1H),7.22-7.26 (m, 1H), 7.43-7.46 (m, 1H), 9.57 (s, 1H) 414

FAB (+) 299 (MH⁺) ¹H-NMR (CDCl₃) δ ppm: 1.30-1.27 (m, 2H), 1.50-1.63 (m,4H), 2.20-2.50 (m, 4H), 3.30 (s, 2H), 6.57 (s, 1H), 6.55-6.60 (br.s,1H), 6.67 (d, J = 8 Hz, 1H), 6.80 (d, J = 8 Hz, 1H), 7.56 (d, J = 3 Hz,1H), 7.68 (s, 1H) 415

FAB (+) 308 (M⁺) 260- 261° C. ¹H-NMR (DMSO-d₆) δ ppm: 4.90 (s, 2H), 6.23(t, J = 8 Hz, 1H), 6.40 (d, J = 10 Hz, 1H), 6.65 (s, 1H), 6.66 (d, J = 8Hz, 1H), 6.86 (d, J = 8 Hz, 1H), 7.43 (ddd, J = 2, 8, 10 Hz, 1H), 7.63(s, 2H), 7.70 (dd, J = 2, 8 Hz, 1H), 9.52 (s, 1H) 416

FAB (+) 309 (MH⁺) >275° C. ¹H-NMR (DMSO-d₆) δ ppm: 4.92 (s, 2H), 6.09(d, J = 8 Hz, 2H), 6.58 (d, J = 1 Hz, 1H), 6.66 (dd, J = 1, 8 Hz, 1H),6.92 (d, J = 8 Hz, 1H), 7.64 (s, 2H), 7.64 (d, J = 8 Hz, 2H), 9.57 (s,1H) 417

233- 235° C. ¹H-NMR (CDCl₃) δ ppm: 2.30 (t, J = 7 Hz, 2H), 3.22 (t, J =7 Hz, 2H), 4.23 (s, 2H), 5.74 (s, 1H), 6.60 (dd, J = 1, 7 Hz, 1H), 6.68(d, J = 1 Hz, 1H), 6.82 (d, J = 7 Hz, 1H), 7.21 (s, 1H), 7.62 (s, 2H),9.43 (s, 1H) 418

FAB (+) 405 (MH⁺) 219- 221° C. ¹H-NMR (CDCl₃) δ ppm: 1.58 (m, 6H), 2.34(m, 4H), 3.25 (d, J = 13 Hz, 1H), 3.31 (d, J = 13 Hz, 1H), 5.65 (s, 1H),6.36 (s, 1H), 6.58 (s, 1H), 6.59 (d, J = 2 Hz, 1H), 6.80 (dd, J = 2, 8Hz, 1H), 6.84 (d, J = 8 Hz, 1H), 7.15-7.32 (m, 4H), 7.54 (d, J = 3 Hz,1H), 7.68 (d, J = 3 Hz, 1H) 419

ESI (+) 314 (MH⁺) 191- 192° C. ¹H-NMR (DMSO-d₆) δ ppm: 2.10-2.33 (m,2H), 2.75 (s, 3H), 2.75-3.05 (m, 6H), 3.33 (s, 2H), 6.68 (s, 1H), 6.71(d, J = 8.1 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H), 7.64 (s, 2H), 9.50 (s,1H) 420

¹H-NMR (DMSO-d₆) δ ppm: 2.96-3.10 (m, 2H), 3.15-3.25 (m, 2H), 3.68-3.80(m, 2H), 3.86-3.94 (m, 2H), 4.11 (d, J = 6.0 Hz, 2H), 6.80 (s, 1H), 7.00(d, J = 8.3 Hz, 1H), 7.05 (d, J = 8.3 Hz, 1H), 7.66 (s, 2H), 9.74 (s,1H), 10.95-11.08 (m, 1H) 421

FAB (+) 371 (MH⁺) ¹H-NMR (CDCl₃) δ ppm: 1.24 (t, J = 7 Hz, 3H),1.70-1.82 (m, 2H), 1.83-1.95 (m, 2H), 1.95-2.10 (m, 2H), 2.25-2.35 (m,1H), 2.75-2.84 (m, 2H), 3.34 (s, 2H), 4.14 (q, J = 7 Hz, 2H), 6.54 (s,1H), 6.64 (d, J = 8 Hz, 1H), 6.82 (d, J = 8 Hz, 1H), 6.95 (s, 1H), 7.58(d, J = 3 Hz, 1H), 7.68 (d, J = 3 Hz, 1H) 422

FAB (+) 315 (MH⁺) ¹H-NMR (DMSO-d₆) δ ppm: 1.30-1.40 (m, 2H), 1.60-1.70(m, 2H), 1.90-2.05 (m, 2H), 2.55-2.65 (m, 2H), 3.25 (s, 2H), 3.35-3.45(m, 1H), 4.53 (m, 1H), 6.68 (d, J = 8 Hz, 1H), 6.73 (s, 1H), 6.82 (d, J= 8 Hz, 1H), 7.62 (s, 2H), 9.42 (br.s, 1H) 423

FAB (+) 329 (MH⁺) 172- 174° C. ¹H-NMR (CDCl₃) δ ppm: 1.55-1.70 (m, 2H),1.83-2.00 (m, 2H), 2.10-2.30 (m, 2H), 2.70-2.80 (m, 2H), 3.20-3.30 (m,1H), 3.35 (s, 3H), 3.40 (s, 2H), 6.58 (s, 1H), 6.62 (s, 1H), 6.78 (d, J= 8 Hz, 1H), 6.82 (d, J = 8 Hz, 1H), 7.57 (s, 1H), 7.68 (s, 1H) 424

FAB (+) 329 (MH⁺) 176- 180° C. ¹H-NMR (CDCl₃) δ ppm: 1.26 (s, 3H),1.50-1.80 (m, 4H), 2.10 (s, 1H), 2.30-2.45 (m, 2H), 2.50- 2.58 (m, 2H),3.43 (s, 2H), 6.77 (d, J = 8 Hz, 1H), 6.83 (d, J = 8 Hz, 1H), 7.25 (s,1H), 7.26 (s, 1H), 7.57 (d, J = 3 Hz, 1H), 7.67 (d, J = 3 Hz, 1H) 425

FAB (+) 342 (MH⁺) 225- 228° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.52 (m, 2H),1.58- 1.68 (m, 2H), 1.83 (m, 2H), 2.00-2.10 (m, 1H), 2.70-2.81 (m, 2H),3.23 (s, 2H), 6.68 (d, J = 8 Hz, 1H), 6.65-6.73 (br.s, 1H), 6.76 (s,1H), 6.81 (d, J = 8 Hz, 1H), 7.18 (br.s, 1H), 7.61 (d, J = 3 Hz, 2H),9.42 (br.s, 1H) 426

FAB (+) 369 (MH⁺) 199- 203° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.60-1.70 (m,2H), 1.70-1.80 (m, 2H), 1.97 (t, J = 7 Hz, 2H), 2.30- 2.38 (m, 2H),2.38-2.43 (m, 2H), 2.53 (t, J = 7 Hz, 2H), 3.29 (s, 2H), 6.69 (d, J = 8Hz, 1H), 6.74 (s, 1H), 6.82 (d, J = 8 Hz, 1H), 7.60 (s, 2H), 9.43 (br.s,1H) 427

FAB (+) 342 (MH⁺), 364 (MNa⁺) ¹H-NMR (DMSO-d₆) δ ppm: 1.50-1.64 (m, 2H),1.64-1.80 (m, 1H), 1.80-1.90 (m, 1H), 2.10-2.30 (m, 1H), 2.30-2.42 (m,1H), 2.42-2.50 (m, 1H), 2.48-2.70 (m, 1H), 2.70-2.82 (m, 1H), 3.18 (s,2H), 5.23 (br.s, 1H), 5.80 (br.s, 1H), 6.68 (d, J = 8 Hz, 1H), 6.73 (s,1H), 6.81 (d, J = 8 Hz, 1H), 7.80 (s, 2H), 9.40 (br.s, 1H) 428

FAB (+) 342 (MH⁺) 209- 211° C, ¹H-NMR (DMSO-d₆) δ ppm: 1.20-1.55 (m,2H), 1.64-1.80 (m, 1H), 1.96-2.08 (m, 2H), 2.60-2.70 (m, 2H), 2.70-2.80(m, 2H), 2.90 (d, J = 12 Hz, 1H), 3.56 (d, J = 12 Hz, 1H), 6.77 (s, 1H),6.78 (d, J = 8 Hz, 1H), 7.82 (d, J = 8 Hz, 1H), 7.00-7.05 (br.s, 1H),7.05-7.12 (br.s, 1H), 7.62 (s, 2H), 9.40 (br.s, 1H) 429

FAB (+) 328 (MH⁺) 194- 197° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.60-1.72 (m,3H), 1.09-1.95 (m, 1H), 1.10-1.22 (m, 1H), 2.80-2.90 (m, 1H), 2.90-2.96(m, 1H), 3.20 (d, J = 8 Hz, 1H), 3.63 (d, J = 8 Hz, 1H), 6.00-6.15(br.s, 1H), 6.70 (d, J = 8 Hz, 1H), 6.78 (s, 1H), 6.83 (d, J = 8 Hz,1H), 7.10-7.20 (br.s, 1H), 7.62 (s, 2H), 9.40 (br.s, 1H) 430

FAB (+) 343 (MH⁺) 148- 152° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.0-1.15 (m, 3H),1.28-1.35 (m, 2H), 1.50-1.62 (m, 2H), 1.75-1.90 (m, 2H), 2.70-2.80 (m,2H), 3.15 (s, 2H), 3.30- 3.45 (m, J = 6 Hz, 2H), 4.32 (m, J = 6 Hz, 1H),6.66 (d, J = 8 Hz, 1H), 6.70 (s, 1H), 6.81 (d, J = 8 Hz, 1H), 7.62 (s,2H), 9.45 (br.s, 1H) 431

FAB (+) 327 (MH⁺) 168- 172° C. ¹H-NMR (CDCl₃) δ ppm: 1.03 (d, J = 8 Hz,6H), 1.04 (s, 3H), 1.20-1.40 (m, 2H), 1.50-1.70 (m, 4H), 2.40-2.50 (m,2H), 3.60 (s, 2H), 6.67 (d, J = 8 Hz, 1H), 6.72 (s, 1H), 6.85 (d, J = 8Hz, 1H), 7.55 (d, J = 3 Hz, 1H), 7.70 (d, J = 3 Hz, 1H), 9.75 (s, 1H)432

FAB (+) 369 (MH⁺) 172- 175° C. ¹H-NMR (CDCl₃) δ ppm: 2.37 (m, 2H), 2.59(t, J = 6 Hz, 2H), 3.24 (br.s, 2H), 3.54 (s, 2H), 3.73 (s, 3H), 6.58 (d,J = 2 Hz, 1H), 6.72 (br.s, 1H), 6.78 (dd, J = 2, 8 Hz, 1H), 6.84 (d, J =8 Hz, 1H), 7.20 (m, 1H), 7.56 (d, J = 3 Hz, 1H), 7.68 (d, J = 3 Hz, 1H)433

FAB (+) 298 (MH⁺) 163- 166° C. ¹H-NMR (CDCl₃) δ ppm: 1.46 (m, 2H), 1.62(m, 4H), 2.42 (br.s, 4H), 3.39 (s, 2H), 6.20 (s, 1H), 6.38 (d, J = 5 Hz,1H), 6.65 (s, 1H), 6.76 (dd, J = 2, 8 Hz, 1H), 6.88 (d, J = 8 Hz, 1H),7.98 (s, 1H), 8.05 (d, J = 5 Hz, 1H)

Example 434N,N-[3-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azapentamethylene]methanesulfonamide

300 mg ofN,N-[3-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azapentamethylene]-methanesulfonamidewas stirred in glacial acetic acid (20 ml) at 65° C. for 3 hours. Afterdistilling off the solvent under reduced pressure, the residue wascrystallized from ethyl acetate/ether to thereby give 240 mg of thetitle compound as yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 2.39-2.44(m, 4H), 2.85(s, 3H), 3.05-3.10(m, 4H),3.32(s, 2H), 6.71(d, J=7.9 Hz, 1H), 6.74(d, J=1.2 Hz, 1H), 6.85(dd,J=1.2, 7.9 Hz, 1H), 7.61-7.64(m, 2H), 9.44(s, 1H)

m.p.: 221-222° C.

MS: FAB(+)377(M⁺)

Examples 435 and 436

The following compounds were obtained by the same method as the one ofExample 434.

Ex. Structural formula MS M.p. NMR 435

FAB (+) 323 (M⁺) 198- 199° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.61-1.72 (m, 2H),1.78-1.84 (m, 2H), 2.14-2.26 (m, 2H), 2.41-2.50 (m, 1H), 2.80-2.90 (m,2H), 3.28 (s, 2H), 6.69 (d, J = 7.9 Hz, 1H), 6.74 (d, J = 1.0 Hz, 1H),6.83 (dd, J = 1.0, 7.9 Hz, 1H), 7.61-7.64 (m, 2H), 9.44 (s, 1H) 436

FAB (+) 421 (MH⁺) 443 (MNa⁺) 172- 173° C. ¹H-NMR (DMSO-d₆) δ ppm:1.34-1.46 (m, 2H), 1.71-1.79 (m, 2H), 1.82-1.93 (m, 2H), 2.60 (s, 6H),2.64-2.71 (m, 2H), 2.89-2.99 (m, 1H), 3.20 (s, 2H), 6.69 (d, J = 7.6 Hz,1H), 6.77 (d, J = 1.4 Hz, 1H), 6.85 (dd, J = 1.4, 7.6 Hz, 1H), 7.15 (d,J = 8.6 Hz, 1H), 7.61 (d, J = 2.5 Hz, 1H), 7.62 (d, J = 2.5 Hz, 1H),9.47 (s, 1H) #

Examples 437 to 465

The following compounds were obtained by the same method as the one ofExample 64 by using anhydrous potassium carbonate as a base as asubstitute for N,N-diisopropylamine.

Ex. Structural formula MS M. p. NMR 437

FAB (+) 461 (MH⁺) 56-57° C. ¹H-NMR(CDCl₃) δ ppm: 1.47-1.58(m, 4H), 1.58-1.65(m, 4H), 1.97(br.d, J=10Hz, 2H), 2.18(br.t, J=10Hz, 2H), 2.77(br.d,J=12Hz, 2H), 3.15(t, 3=6Hz, 4H), 3.22(m, 1H), 3.33(s, 2H), 4.27(d,J=9Hz, 1H), 6.52(d, J=2Hz, 1H), 6.73(dd, J=2, # 8Hz, 1H), 6.74(br.s,1H), 6.82(d, J=8Hz, 1H), 7.56(d, J=3Hz, 1H), 7.68(d, J=3Hz, 1H) 438

FAB (+) 463 (MH⁺) 189-190° C. ¹H-NMR(CDCl₃) δ ppm: 1.54(br.t, J=10Hz,2H), 1.99(br.d, J=10Hz, 2H), 2.08(br.t, J=10Hz, 2H), 2.69(br.d, J=10Hz,2H), 3.18(t, J=5Hz, 4H), 3.25(m, 1H), 3.33(s, 2H), 3.74(t, J=5Hz, 4H),4.35(d, J=9Hz, 1H), 6.52(d, J=2Hz, 1H), # 6.69(br.s, 1H), 6.73(dd, J=2,8Hz, 1H), 6.82(d, J=8Hz, 1H), 7.56(d, J=3Hz, 1H), 7.69(d, J=3Hz, 1H) 439

FAB (+) 437 (MH⁺) 164-166° C. ¹H-NMR(CD₃OD) δ ppm: 1.56-1.66(m. 2H),1.98- 2.04(m, 2H), 2.24-2.33(m, 2H), 2.94-2.98(m, 2H), 3.25(t, J=6Hz,2H), 3.14- 3.23(m, 1H), 3.49(s, 2H), 3.62(t, J=6Hz, 2H), 6.67(d, J=2Hz,1H), 6.79(dd, J=2, 8Hz, 1H), 6.84(d, J=8Hz, 1H), # 7.57(d, J=3Hz, 1H),7.58(d, J=3Hz, 1H) 440

FAB (+) 371 (MH⁺) 187-188° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.05(s, 6H),1.05-1.18(m, 2H), 1.25(d, J=6Hz, 2H), 1.34-1.45(m, 1H), 1.64- 1.70(m,2H), 1.80-1.90(m, 2H), 2.65-2.70(m, 2H), 3.20(s, 2H), 4.12(s, 1H),6.68(dd, J=1, 7Hz, 1H), 6.74(d, J=1Hz, 1H), 6.82(d, # J=7Hz, 1H),7.62(d, J=3Hz, 1H), 7.63(d, J=3Hz, 1H), 9.43(br.s, 1H) 441

FAB (+) 383 (MH⁺) >275° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.49(d, J=11Hz, 2H),1.81(t, J=11Hz, 2H), 2.24(t, J=11Hz, 2H), 2.63(d, J=11Hz, 2H), 3.29(s,2H), 6.69(dd, J=2, 8Hz, 1H), 6.78(d, J=2Hz, 1H), 6.83(d, J=8Hz, 1H),7.62(d, J=3Hz, 1H), 7.63(d, J=3Hz, 1H), 8.44(s, 1H), # 9.45(s, 1H),10.62(s, 1H) 442

FAB (+) 465 (MH+) 194-196° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.32-1.42(m, 2H),1.73- 1.78(m, 2H), 1.86-1.92(m, 2H), 2.64-2.72(m, 2H), 2.95-3.00(m, 1H),3.22(s, 2H), 3.61(s, 3H), 3.62(d, J=7Hz, 2H), 6.67(dd, J=1, 8Hz, 1H),6.73(d, J=1Hz, 1H), 6.82(d, J=8Hz, 1H), # 6.95(d, J=7Hz, 1H), 7.32(t,J=7Hz, 1H), 7.62(d, J=3Hz, 1H), 7.63(d, J=3Hz, 1H), 9.44(s, 1H) 443

FAB (+) 420 (MH⁺) 198-199° C. ¹H-NMR(CDCl₃) δ ppm: 1.54(dq, J=3, 11Hz,2H), 1.97(br.d, J=11Hz, 2H), 2.08(t, J=11Hz, 2H), 2.75(br.s, 2H), 2,78(s, 6H), 3.22(br.s, 1H), 3.34(s, 2H), 4.02(d, J=7Hz, 1H), 6.05(s, 1H),6.38(d, J=5Hz, 1H), 6.56(s, 1H), 6.77(dd, # J=2, 8Hz, 1H), 6.88(d,J=8Hz, 1H), 8.00(s, 1H), 8.24(d, J=5Hz, 1H), 444

FAB (+) 369 (MH⁺) 180-182° C. ¹H-NMR(CDCl₃) δ ppm: 1.68(m, 4H), 2.32(m,2H), 2.40(s, 2H), 2.46(m, 2H), 3.33(s, 2H), 4.05(s, 2H), 6.38(s, 1H),6.50(s, 1H), 6.75(d, J=8Hz, 1H), 6.84(d, J=8Hz, 1H), 7.58(d, J=3Hz, 1H),7.68(d, J=3Hz, 1H) 445

FAB (+) 368 (MH⁺) 211-212° C. ¹H-NMR(CDCl₃) δ ppm: 1.67(t, J=6Hz, 4H),2.41(s, 2H), 2.35(br.s, 2H), 2.43(br.s, 2H), 3.18(s, 2H), 3.24(s, 2H),5.47(br.s, 1H), 6.45(br.s, 1H), 6.53(d, J=2Hz, 1H), 6.75(dd, J=2, 8Hz,1H), 6.83(d, J=8Hz, 1H), 7.57(d, J=3Hz, 1H), # 7.69(d, J=3Hz, 1H) 446

FAB (+) 444 (MH⁺) 155-157° C. ¹H-NMR(CDCl₃) δ ppm: 1.57(m, 2H), 2.0(m,4H), 2.2(br.s, 2H), 2.79(s, 6H), 3.25(br.s, 1H), 3.35(s, 2H), 6.64(br.s,1H), 6.78(dd, J=2, 8Hz, 1H), 6.83(d, J=8Hz, 1H), 6.87(d, J=5Hz, 1H),7.81(d, J=5Hz, 1H) 447

FAB (+) 422 (MH⁺) 205-210° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.36-1.48(m, 2H),1.73- 1.80(m, 2H), 1.89-1.98(m, 3H), 2.61(s, 6H), 2.64- 2.74(m, 2H),3.24(s, 2H), 6.93(s, 1H), 7.19(s, 1H), 7.64(s, 1H), 7.67(s, 1H), 9.54(s,1H) 448

FAB (+) 419 (MH⁺) 119-122° C. ¹H-NMR(CDCl₃) δ ppm: 1.46(m, 2H),1.86-1.96(m, 1H), 1.96-2.03(m, 2H), 2.05-2.16(m, 2H), 2.76- 2.87(m, 2H),2.96(s, 3H), 3.33(s, 2H), 5.89-5.96(m, 1H), 6.52(d, J=1.7Hz, 1H),6.69-6.72(br.s, 1H), 6.74(dd, J=1.7, 8.3Hz, 1H), 6.82(d, J=8.3Hz, # 1H),7.56(d, J=3.0Hz, 1H), 7.69(d, J=3.0Hz, 1H), 8.14(d, J=5.6Hz, 1H) 449

FAB (+) 404 (M⁺) 405 (MH⁺) 212-214° C. ¹H-NMR(DMSO-d₆) δ ppm:2.32-2.37(m, 2H), 2.39-2.44(m, 2H), 2.84(s, 3H), 3.33(s, 2H),3.48-3.55(m, 4H), 6.71(dd, J=1.6, 8.6Hz, 1H), 6.75(d, J=1.6Hz, 1H),6.86(d, J=8.6Hz, 1H), 7.61-7.64(m, 2H), # 8.07(s, 1H), 9.46(s, 1H) 450

FAB (+) 392 (M⁺) 208-210° C. ¹H-NMR(DMSO-d₆) δ ppm: 2.36-2.41(m, 4H),2.49(d, J=5.1Hz, 3H), 2.99-3.05(m, 4H), 3.30(br.s, 2H), 6.70(d, J=8.0Hz,1H), 6.77(d, J=2.2Hz, 1H), 6.84(dd, J=2.2, 8.0Hz, 1H), 7.10(q, J=5.1Hz,1H), 7.63(s, 2H), 9.45(s, 1H) 451

FAB (+) 378 (M⁺) 215-217° C. (decompose) ¹H-NMR(DMSO-d₆) δ ppm:2.37-2.43(m, 4H), 2.91-2.96(m, 4H), 3.30(s, 2H), 6.70(d, J=8.4Hz, 1H),6.75- 6.79(m, 3H), 6.84(dd, J=2.0, 8.4Hz, 1H), 7.61-7.64(m, 2H), 9.47(s,1H) 452

FAB (+) 385 (MH⁺) 186-190° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.56-1.70(m, 4H),1.85- 1.97(m, 2H), 2.70-2.78(m, 2H), 3.25(s, 2H), 3.36- 3.47(m, 1H),6.68(d, J=7.9Hz, 1H), 6.73(s, 1H), 6.83(d, J=7.9Hz, 1H), 7.60-7.64(m,2H), 8.60-8.80(br.s, 2H), 8.84-9.02(br.s, 1H), # 9.46(s, 1H) 453

FAB (+) 420 (NH⁺) 202-206° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.56-1.68(m, 4H),1.80- 1.90(m, 2H), 2.07-2.17(m, 1H), 2.77-2.84(m, 2H), 3.25(br.s, 2H),6.47(br.s, 2H), 6.69(d, J=8.0Hz, 1H), 6.76(s, 1H), 6.83(d, J=8.0Hz, 1H),7.20(br.s, 1H), 7.62(s, 2H), 8.13(br.s, # 1H), 9.45(s, 1H) 454

FAB (+) 419 (MH⁺) 204-209° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.56-1.69(m, 4H),1.80- 1.89(m, 2H), 2.14-2.23(m, 1H), 2.76-2.82(m, 2H), 2.84(s, 3H),3.24(br.s, 2H), 6.68(dd, J=1.3, 8.3Hz, 1H), 6.76(d, J=1.3Hz, 1H),6.82(d, J=8.3Hz, 1H), 7.62(s, 2H), 7.63(br.s, 1H), # 8.38(br.s, 1H),9.45(s, 1H) 455

FAB (+) 421 (MH⁺) 198-203° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.35-1.48(m, 2H),1.71- 1.80(m, 2H), 1.85-1.95(m, 2H), 2.60(s, 6H), 2.65- 2.73(m, 2H),2.90-3.00(m, 1H) 3.23(s, 2H), 6.73(dd, J=1.3, 7.7Hz, 1H), 6.78(d,J=1.3Hz, 1H), 6.86(d, J=7.7Hz, 1H), 7.19(d, J=7.4Hz, 1H), # 7.92(s, 1H),8.22(s, 1H), 9.78(s, 1H) 456

FAB (+) 333 (MH⁺) 219-220° C. ¹H-NMR(CDCl₃) δ ppm: 3.76(s, 2H), 3.92(s,4H), 6.58(br.s, 1H), 6.64(br.s, 1H), 6.83- 6.88(m, 2H), 7.19(s, 4H),7.56(d, J=2.9Hz, 1H), 7.63(d, J=2.9Hz, 1H) 457

ESI (+) 376 (MH⁺) 241-243° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.34-1.48(m, 2H),1.72- 1.82(m, 2H), 1.86-1.98(m, 2H), 2.64-2.74(m, 2H), 2.88(s, 3H),3.20-3.14(m, 1H), 3.21(s, 2H), 6.5- 6.65(m, 2H), 6.65-6.70(m, 1H),7.0-7.1(m, 1H), 7.20-7.28(m, 1H), 7.42- # 7.48(m, 1H), 9.57(s, 1H) 458

ESI (+) 406 (MH⁺) 218-221° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.0-1.16(m, 2H),1.30- 1.42(m, 1H), 1.58-1.68(m, 2H), 1.78-1.88(m, 2H), 2.7-2.8(m, 2H),2.78(t, J=7Hz, 2H), 2.84(s, 3H), 3.23(s, 2H), 6.65-6.70(m, 1H), 6.74(s,1H), 6.82(d, J=8Hz, 1H), 6.96(t, # J=6Hz, 1H), 7.60-7.65(m, 2H), 9.43(s,1H) 459

ESI (+) 370 (MH⁺) 168-170° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.0-1.2(m, 2H),1.25- 1.45(m, 1H), 1.50-1.65(m, 2H), 1.77(s, 3H), 1.75- 1.90(m, 2H),2.68-2.80(m, 2H), 2.89(t, J=7Hz, 2H), 3.22(br.s, 2H), 6.6- 6.75(m, 1H),6.74(s, 1H), 6.75-6.90(m, 1H), 7.62(d, J=3Hz, 1H), 7.63(d, # J=3Hz, 1H),7.79(m, 1H), 9.43(s, 1H) 460

ESI (+) 421 (MH⁺) 202-203° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.35-1.50(m, 2H),1.7- 1.8(m, 2H), 1.80-1.98(m, 2H), 2.60(s, 6H), 2.6- 2.75(m, 2H),2.9-3.0(m, 1H), 3.21(s, 2H), 6.66(d, J=8Hz, 1H), 6.72(s, 1H), 6.81(d,J=8Hz, 1H), 7.18(d, J=8Hz, 1H), 7.61(d, J=3Hz, # 1H), 7.62(d, J=3Hz,1H), 9.43(s, 1H) 461

ESI (+) 406 (MH⁺) 216-218° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.32-1.48(m, 2H),1.70- 1.80(m, 2H), 1.82-1.94(m, 2H), 2.41(d, J=5Hz, 3H), 2.64-2.74(m,2H), 2.84- 2.96(m, 1H), 3.23(s, 2H), 6.59(q, J=5Hz, 1H), 6.67(dd, J=1,8Hz, 1H), 6.70(dd, J=1, 8Hz, 1H), # 6.78(d, J=1Hz, 1H), 6.83(d, J=8Hz,1H), 6.87(d, J=8Hz, 1H), 7.25(dd, J=1, 8Hz, 1H), 7.78(dd, J=1, 8Hz, 1H),9.14(s, 1H) 462

ESI (+) 391 (MH⁺) 219-222° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.3-1.46(m, 2H),1.70- 1.84(m, 2H), 1.82-1.94(m, 2H), 2.41(d, J=5Hz, 3H), 2.64-2.78(m,2H), 2.78- 2.96(m, 1H), 3.21(s, 2H), 6.5-6.65(m, 3H), 6.68(d, J=8Hz,1H), 6.87(d, J=7Hz, 1H), 7.24(d, J=3Hz, 1H), # 7.44(d, J=3Hz, 1H),9.57(s, 1H) 463

ESI (+) 446 (MH⁺) 199-201° C. ¹H-NMR(DMSO-d₆) δ pm: 1.53-1.60(m, 2H),1.7- 1.8(m, 2H), 1.9-2.3(m, 2H), 2.66-2.80(m, 2H), 3.25(s, 2H),3.2-3.4(m, 1H), 6.67(d, J=8Hz, 1H), 6.73(s, 1H), 6.83(d, J=8Hz, 1H),7.62(s, 2H), 9.45(s, 2H) 464

FAB (+) 381 (MH⁺) 159-162° C. ¹H-NMR(DMSO-d₆) δ pm: 2.29(m, 2H), 2.39(m,2H), 2.44(m, 2H), 2.85(t, J=7Hz, 2H), 2.94(br.s, 2H), 3.32(s, 2H),4.22(t, J=7Hz, 2H), 6.72(d, J=8Hz, 1H), 6.76(s, 1H), 6.85(d, J=8Hz, 1H),7.63(m, 2H), 9.45(s, 1H) 465

FAB (+) 359 (MH⁺) 182-185° C. ¹H-NMR(DMSO-d₆) δ pm: 1.16-1.35(m, 3H),1.44(m, 1H), 1.63(br.d, J=12Hz, 1H), 1.78(br.q, J=8Hz, 2H), 2.77(m, 2H),3.17-3.38(m, 3H), 3.20(s, 2H), 4.13(d, J=6Hz, 1H), 4.37(t, J=6Hz, 1H),6.67(d, J=8Hz, 1H), 6.75(s, 1H), 6.81(d, J=8Hz, # 1H), 7.63(m, 2H),9.43(s, 1H)

Example 466N,N-[3-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azapentamethylene]-N′,N′-dimethylsulfamide

The title compound was obtained as yellow crystals by treating3-benzyl-3-azapentamethylene]-N′,N′-dimethylsulfamide and8-chloromethyl-10H-pyrazino[2,3-b][1,4]benzothiazine by the same methodas the one of Example 17.

¹H-NMR(CDCl₃) δ ppm: 2.46-2.55(m, 4H), 2.83(s, 6H), 3.25-3.35(m, 4H),3.38(s, 2H), 6.44(br.s, 1H), 6.54(s, 1H), 6.76(d, J=8.0 Hz, 1H), 6.84(d,J=8.0 Hz, 1H), 7.58(d, J=2.8 Hz, 1H), 7.70(d, J=2.8 Hz, 1H)

m.p.: 171-173° C.

Example 467N-[1-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-azetidin-3-ylmethyl]methanesulfonamide

The title compound was obtained as yellow crystals by treatingN-[(1-diphenylmethylazetidin-3-yl)methyl]methanesulfoamide and8-chloromethyl-10H-pyrazino[2,3-b][1,4]benzothiazine by the same methodas the one of Example 64.

¹H-NMR(DMSO-d₆) δ ppm: 2.52(br.s, 1H), 2.87(s, 3H), 2.88(br.s, 2H),3.10(t, J=7 Hz, 2H), 3.23(br.s, 2H), 3.41(br.s, 2H), 6.68(d, J=8 Hz,1H), 6.69(s, 1H), 6.82(d, J=8 Hz, 1H), 7.07(t, J=5 Hz, 1H), 7.62(d, J=3Hz, 1H), 7.63(d, J=3 Hz, 1H), 9.44(s, 1H)

MS: FAB(+)378(MH⁺)

m.p.: 84-88° C.

Examples 468 to 497

The following compound was obtained by the same method as the one ofExample 467.

Ex. Structural formula MS M.p. NMR 468

FAB (+) 393 (MH⁺) 173- 176° C. ¹H-NMR (DMSO-d₆) δ ppm: 2.41 (d, J = 5Hz, 3H), 2.60 (br.s, 3H), 2.96 (t, J = 6 Hz, 2H), 3.44 (br.s, 2H), 3.57(br.s, 2H), 6.68 (d, J = 8 Hz, 1H), 6.69 (s, 1H), 6.84 (d, J = 8 Hz,1H), 6.94 (s, 1H), 7.62 (d, J = 3 Hz, 1H), 7.63 (d, J = 3 Hz, 1H), 9.48(s, 1H)

Example

The following compounds were obtained by the same method as the one ofExample 66.

Ex. Structural formula MS M.p. NMR 469

FAB(+) 452(MH⁺) 190- 191° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.10-1.24(m, 6H),1.54- 1.66(m, 4H), 2.0(m, 1H), 2.36(m, 2H), 2.82(d, J=10Hz, 2H), 3.30(s,2H), 6.72(d, J=8Hz, 1H), 6.75(d, J=2Hz, 1H), 6.85(dd, J=2, 8Hz, 1H),7.63(m, 2H), 9.48(br.s, 1H), 11.61(br.s, 1H) 470

FAB(+) 519(MH⁺) 181- 184° C. ¹H-NMR (CDCl₃) δ ppm: 1.40-1.80(m, 12H),1.90- 2.40(m, 9H), 2.27(d, J=6.8Hz, 2H), 2.34(s, 3H), 2.52-2.64(m, 1H),3.18-3.27(m, 2H), 3.30(s, 2H), 4.02-4.12(m, 1H), 6.39(br.s, 1H), 6.54(s,1H), 6.74(d, J=8.0Hz, 1H), 6.82(d, J=8.0Hz, 1H), 7.57(d, J=2.8Hz, 1H),7.69(d, J=2.8Hz, 1H) 471

ESI (+) 342(MH⁺) 142- 143° C. ¹H-NMR (CDCl₃ ) δ ppm: 2.31-2.35(m, 2H),2.44- 2.49(m, 2H), 2.51-2.55(m, 2H), 2.55-2.60(m, 2H), 3.36(s, 2H),3.82(s, 3H), 6.54(d, J=7.9Hz, 1H), 6.65-6.69(br.s, 1H), 6.77(dd, J=1.5,7.9Hz, 1H), 6.83(d, J=79Hz, 1H), 7.58(d, J=3.1Hz, 1H), 7.69(d, J=3.1Hz,1H) 472

FAB(+) 394(M⁺) 285- 288° C. (decom- pose) ¹H-NMR (DMSO-d₆) δ ppm:2.46(br.m, 4H), 3.37(s, 2H), 3.68(br.m, 4H), 6.74(d, J=7.9Hz, 1H),6.77(s, 1H), 6.86(d, J=7.9Hz, 1H), 7.64(d, J=2.9Hz, 1H), 7.65(d,J=2.9Hz, 1H), 7.70(s, 2H), 9.48(s, 1H) 473

FAB(+) 409(MH⁺) >300° C. ¹H-NMR (DMSO-d₆) δ ppm: 2.43(m, 4H), 3.16(d,J=4.6Hz, 3H), 3.35(s, 2H), 3.64(br.s, 4H), 6.73(dd, J=1.5, 7.9Hz, 1H),6.76(d, J=1.5Hz, 1H), 6.86(d, J=7.9Hz, 1H), 7.61(m, 1H), 7.64(d,J=2.7Hz, 1H), 7.65(d, J=2.7Hz, 1H), 9.48(s, 1H) 474

FAB(+) 423(MH⁺) 296- 300° C. (decom- pose) ¹H-NMR (DMSO-d₆) δ ppm:2.45(m, 4H), 3.15(s, 6H), 3.34(s, 2H), 3.61(m, 4H), 6.73(d, J=7.9Hz,1H), 6.77(br.s, 1H), 6.86(d, J=7.9Hz, 1H), 7.64(br.s, 2H), 9.47(s, 1H)475

ESI(+) 341(MH⁺) 192- 195°C. ¹H-NMR (CDCl₃) δ ppm: 1.70(s, 1H),1.86-1.97(m, 4H), 2.16-2.27(m, 2H), 2.70-2.80(m, 2H), 2.82- 2.90(m, 2H),3.51(s, 2H), 4.05-4.11(m, 1H), 6.54(br.s, 1H), 6.68(dd, J=2, 8Hz, 1H),6.79(d, J=8Hz, 1H), 7.00(br.s, 1H), 7.55(d, J=2.8Hz, 1H), 7.65(d,J=2.8Hz, 1H) 476

¹H-NMR (CDCl₃) δ ppm: 0.53-0.59(m, 2H), 0.97- 1.0(m, 1H), 1.80-2.08(m,2H), 1.95(br.s, 1H), 2.12- 2.24(m, 2H), 2.58-2.74(m, 2H), 3.21-3.50(m,4H), 6.56(s, 1H), 6.71-6.76(m, 2H), 6.81(d, J=8.0Hz, 1H), 7.56(d,J=2.4Hz, 1H), 7.68(d, J=2.4Hz, 1H) 477

ESI(+) 355(MH⁺) 57- 60° C. ¹H-NMR (CDCl₃) δ ppm: 0.16-0.22(m, 1H), 0.50-0.55(m, 1H), 0.90-1.00(m, 1H), 1.35-1.75(m, 5H), 2.30-2.50(m, 4H),3.37(s, 2H), 3.50-3.72(m, 2H), 6.59(s, 1H), 6.71(br.s, 1H), 6.77(dd,J=1.6, 8.0Hz, 1H), 6.83(d, J=8.0Hz, 1H), 7.58(d, J=2.8Hz, 1H), 7.69(d,J=2.8Hz, 1H) 478

ESI(+) 355(MH⁺) oil ¹H-NMR (CDCl₃) δ ppm: 1.20-1.32(m, 1H), 1.35-1.64(m, 1H), 1.82-1.88(m, 1H), 2.00-2.16(m, 3H), 2.31-2.40(m, 2H), 2.57-2.86(m, 4H), 3.40-3.78(m, 4H), 6.60-6.86(m, 4H), 7.56(d, J=2.8Hz, 1H),7.68-7.69(m, 1H) 479

FAB(+) 353(MH⁺) ¹H-NMR (CDCl₃) δ ppm: 2.71-2.82(m, 4H), 3.56(s, 2H),3.66(s, 2H), 6.43(s, 1H), 6.62(s, 1H), 6.79(d, J=5.0Hz, 1H), 6.81(d,J=8.0Hz, 1H), 6.85(d, J=8.0Hz, 1H), 7.09(d, J=5.0Hz, 1H), 7.57(d,J=2.8Hz, 1H), 7.68(d, J=2.8Hz, 1H) 480

FAB(+) 337(MH⁺) 168- 172° C. ¹H-NMR (CDCl₃) δ ppm: 2.54(t, J=5.6Hz, 2H),2.72(t, J=5.6Hz, 2H), 3.50(s, 2H), 3.56(s, 2H), 6.24(d, J=2.0Hz, 1H),6.49(br.s, 1H), 6.60(s, 1H), 6.81(d, J=8.0Hz, 1H), 6.85(d, J=8.0Hz, 1H),7.26(d, J=2.0Hz, 1H), 7.57(d, J=2.8Hz, 1H), 7.68(d, J=2.8Hz, 1H)

Examples

Starting with known compounds, the following compounds were obtained bythe same method as the one of Example 63.

Ex. Structural formula MS M.p. NMR 481

FAB(+) 341(M⁺) ¹H-NMR (DMSO-d₆) δ ppm: 1.95(s, 3H), 2.22- 2.27(m, 2H),2.29- 2.34(s, 2H), 3.29(s, 2H), 3.36-3.43(m, 4H), 6.70(d, J=8.2Hz, 1H),6.75(s, 1H), 6.84(d, J=8.2Hz, 1H), 7.61- 7.64(m, 2H), 9.45(s, 1H) 482

FAB(+) 391(M⁺) 392(MH⁺) 158- 160° C. ¹H-NMR (DMSO-d₆) δ ppm:1.71-1.80(m, 2H), 2.54-2.59(m, 2H), 2.59-2.63(m, 2H), 2.87(s, 3H), 3.28-3.34(m, 4H), 3.43(s, 2H), 6.71(d, J=8.3Hz, 1H), 6.78(s, 1H), 6.84(d,J=8.3Hz, 1H), 7.61-7.64(m, 2H), 9.47(s, 1H) 483

FAB(+) 298(MH⁺) 238° C. (decom- pose) ¹H-NMR (DMSO-d₆) δ ppm:1.84-1.92(m, 2H), 2.18-2.24(m, 2H), 2.24-2.29(m, 2H), 4.48(s, 2H),6.68(d, J=1.3Hz, 1H), 6.76(dd, J=1.3, 8.6Hz, 1H), 6.95(d, J=8.6Hz, 1H),7.64(s, 2H), 8.43(d, J=6.5Hz, 1H), 9.58(s, 1H), 10.08-10.14(br.s, 1H)484

ESI(+) 317(MH⁺) 241- 242° C. (decom- pose) ¹H-NMR (DMSO-d₆) δ ppm:2.95-3.04(m, 1H), 3.16-3.25(m, 1H), 3.26-3.35(m, 1H), 3.55-3.65(m, 1H),4.04-4.23(m, 4H), 5.18-5.26(m, 1H), 5.30-5.39(m, 1H), 6.81(s, 1H),6.98(d, J=8.5Hz, 1H), 7.02(d, J=8.5Hz, 1H), 7.66(s, 2H), 9.68(s, 1H),10.67-10.80(br.s, 1H) 485

FAB(+) 352(MH⁺) 238- 241° C. (decom- pose) ¹H-NMR (DMSO-d₆) δ ppm:2.31-2.36(m, 2H), 2.38-2.43(m, 2H), 3.29(s, 2H), 3.43- 3.49(m, 4H),6.71(d, J=7.4Hz, 1H), 6.75(s, 1H), 6.85(d, J=7.4Hz, 1H), 7.62(d,J=2.3Hz, 1H), 7.63(d, J=2.3Hz, 1H), 8.40(s, 1H), 9.46(s, 1H) 486

ESI(+) 366 (MH⁺), 388 (MNa⁺) 234° C. (decom- pose) ¹H-NMR (DMSO-d₆) δppm: 2.30-2.36(m, 2H), 2.33(s, 3H), 2.37- 2.42(m, 2H), 3.31(s, 2H),3.49-3.54(m, 2H), 3.58-3.63(m, 2H), 6.70(dd, J=1.8, 7.8Hz, 1H), 6.74(d,J=1.8, Hz, 1H), 6.85(d, J=7.8Hz, 1H), 7.62(d, J=2.7Hz, 1H), 7.63(d,J=2.7Hz, 1H), 9.39- 9.53(br.s, 1H) 487

FAB(+) 327(MH⁺) 133- 135° C. ¹H-NMR (CDCl₃) δ ppm: 1.50-1.75(m, 10H),2.48- 2.60(m, 4H), 3.44(s, 2H), 6.49(br.s, 1H), 6.59(s, 1H),6.80-6.84(m, 2H), 7.56(d, J=2.8Hz, 1H), 7.68(d, J=2.8Hz, 1H) 488

FAB(+) 313(MH⁺) 161- 163° C. ¹H-NMR (CDCl₃) δ ppm: 1.58-1.80(m, 8H),2.60- 2.70(m, 4H), 3.53(s, 2H), 6.57(br.s, 1H), 6.80(s, 1H), 6.77(d,J=8.0Hz, 1H), 6.82(d, J=8.0Hz, 1H), 7.57(d, J=2.8Hz, 1H), 7.68(d,J=2.8Hz, 1H) 489

FAB(+) 271(MH⁺) 158- 161° C. ¹H-NMR (CDCl₃) δ ppm: 2.11(quint, J=6.8Hz,2H), 3.23(t, J=6.8Hz, 4H), 3.44(s, 2H), 6.49(d, J=1.6Hz, 1H), 6.54(br.s,1H), 6.72(dd, J=1.6, 8.0Hz, 1H), 6.82(d, J=8.0Hz, 1H), 7.57(d, J=2.8Hz,1H), 7.68(d, J=2.8Hz, 1H) 490

FAB(+) 293(M⁺) 230- 232° C. ¹H-NMR (DMSO-d₆) δ ppm: 5.67(s, 2H), 6.68(d,J=1Hz, 1H), 6.84(dd, J=1, 7Hz, 1H), 6.98(d, J=7Hz, 1H), 7.65(s, 2H),8.19(dd, J=6, 7Hz, 2H), 8.64(t, J=7Hz, 1H), 9.11(d, J=6Hz, 2H), 9.61(s,1H) 491

FAB(+) 312(M⁺) 186- 188° C. ¹H-NMR (DMSO-d₆) δ ppm: 2.32(t, J=6Hz, 4H),2.64(t, J=6Hz, 4H), 3.32(s, 2H), 6.75(d, J=8Hz, 1H), 6.80(s, 1H),6.86(d, J=8Hz, 1H), 7.63(m, 2H), 9.47(s, 1H) 492

FAB(+) 315(M⁺) 144- 146° C. ¹H-NMR (CD₃OD) δ ppm: 3.12(s, 3H), 3.34-3.41(br.s, 2H), 3.54- 3.61(ddd, J=5, 8, 13Hz, 2H), 4.01-4.07(m, 4H),4.49(s, 2H), 6.78(d, J=2Hz, 1H), 6.95(dd, J=2, 8Hz, 1H), 7.01(d, J=8Hz,1H), 7.62(s, 2H) 493

FAB(+) 345(MH⁺) 170- 173° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.29(br.d, J=12Hz,2H), 1.54(br.t, J=12Hz, 2H), 2.22(br.t, J=10Hz, 2H), 2.43(m, 2H),3.12(s, 2H), 3.23(s, 2H), 4.13(br.s, 1H), 4.51(br.s, 1H), 6.68(d, J=8Hz,1H), 6.75(s, 1H), 6.82(d, J=8Hz, 1H), 7.62(s, 2H), 9.43(s, 1H) 494

FAB(+) 347(MH⁺) 208- 210° C. ¹H-NMR (CDCl₃) δ ppm: 1.96-2.07(m, 2H),2.81(t, J=6.0Hz, 2H), 3.30(t, J=6.0Hz, 2H), 4.31(s, 2H), 6.42(br.s, 1H),6.44(s, 1H), 6.59(d, J=7.2Hz, 1H), 6.61(d, J=7.2Hz, 1H), 6.74(d,J=8.0Hz, 1H), 6.84(d, J=8.0Hz, 1H), 6.96- 7.20(m, 2H), 7.50(d, J=2.8Hz,1H), 7.65(d, J=2.8Hz, 1H) 495

ESI(+) 342(MH⁺) 265- 271° C. (decom- pose) ¹H-NMR (CD₃OD) δ ppm:2.51(br.t, J=5.1Hz, 4H), 3.41(s, 2H), 3.47(br.t, J=5.1Hz, 4H), 6.70(d,J=1.6Hz, 1H), 6.79(dd, J=1.6, 7.9Hz, 1H), 6.82(d, J=7.9Hz, 1H), 7.57(d,J=2.9Hz, 1H), 7.58(d, J=2.9Hz, 1H) 496

FAB(+) 347(MH⁺) 188- 191° C. ¹H-NMR (CDCl₃) δ ppm: 2.73(t, J=6.0Hz, 2H),2.91(t, J=6.0Hz, 2H), 3.52(s, 2H), 3.60(s, 2H), 6.57(br.s, 1H), 6.63(s,1H), 6.83(d, J=8.0Hz, 1H), 6.85(d, J=8.0Hz, 1H), 6.99(d, J=8.0Hz, 1H),7.08-7.17(m, 3H), 7.55(d, J=2.8Hz, 1H), 7.63(d, J=2.8Hz, 1H) 497

FAB(+) 353(MH⁺) 182- 184° C. ¹H-NMR (CDCl₃) δ ppm: 2.79(t, J=6.0Hz, 2H),2.89(t, J=6.0Hz, 2H), 3.54(s, 2H), 3.55(s, 2H), 6.45(br.s, 1H), 6.62(s,1H), 6.70(d, J=4.8Hz, 1H), 6.82(d, J=8.0Hz, 1H), 6.86(d, J=8.0Hz, 1H),7.08(d, J=4.8Hz, 1H), 7.57(d, J=2.8Hz, 1H), 7.67(d, J=2.8Hz, 1H)

Example 498N-Methyl-2-[1-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)piperidin-4-yl]ethanesulfonamide

The title compound was obtained as yellow crystals by treatingN-methyl-2-(piperidin-4-yl)ethanesulfonamide acetate and8-chloromethyl-10H-pyrazino[2,3-b][1,4]benzothiazine by the same methodas the one of Example 131.

¹H-NMR(CDCl₃) δ ppm: 1.28(dq, J=3, 11 Hz, 2H), 1.39(m, 1H), 1.67(m, 2H),1.75(m, 2H), 1.94(dt, J=1, 11 Hz, 2H), 2.81(d, J=6 Hz, 3H), 2.95(br.d,J=11 Hz, 2H), 3.04(m, 2H), 3.32(s, 2H), 4.18(q, J=6 Hz, 1H), 6.51(br.s,1H), 6.53(d, J=2 Hz, 1H), 6.75(dd, J=2, 8 Hz, 1H), 6.83(d, J=8 Hz, 1H),7.57(d, J=3 Hz, 1H), 7.69(d, J=3 Hz, 1H)

MS: ESI 420.1(MH⁺)

m.p.: 195-198° C.

Examples 499 and 500

The following compounds were obtained by the same method as the one ofExample 498.

Ex. Structural formula MS M.p. NMR 499

FAB(+) 434(MH⁺) 188- 190° C. ¹H-NMR(CDCl₃) δ ppm: 1.27(dq, J=3, 11Hz,2H), 1.39(m, 1H), 1.6(m, 2H), 1.75(m, 2H), 1.92(dt, J=1, 11Hz, 2H),2.85(br.d, J=11Hz, 2H), 2.86(s, 6H), 2.93(m, 2H), 3.32(s, 2H), 6.51(d, #J=2Hz, 1H), 6.60(br.s, 1H), 6.75(dd, J=2, 8Hz, 1H), 6.83(d, J=8Hz, 1H),7.58(d, J=3Hz, 1H), 7.69(d, J=3Hz, 1H) 500

FAB(+) 476(MH⁺) 193- 194° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.14(m, 2H),1.31(m, 1H), 1.53-1.64(m, 4H), 1.83(m, 2H), 2.74(br.d, J=8Hz, 2H),3.03(m, 2H), 3.12(t, J=6Hz, 4H), 3.23(s, 2H), 3.61(t, J=6Hz, 4H),6.67(d, J= # 8Hz, 1H), 6.74(s, 1H), 6.83(d, J=8Hz, 1H), 7.63(s, 2H),9.44(s, 1H)

Example 501[1-(10H-Pyrazino[2,3-b][1,4]-benzothiazin-8-ylmethyl)-piperidine-4-(N-cyano)carboxamidine

To a solution of 450 mg ofmethyl[1-(10H-pyrazino[2,3-b][1,4]-benzothiazin-8-ylmethyl)-piperidine-4-carboximidatein dry tetrahydrofuran (10 ml) were added 1.0 ml of triethylamine and1.0 g of cyanamide and the resulting mixture was heated to 45° C. for 2hours. Then the reaction mixture was distributed into water and ethylacetate. The organic layer was extracted, washed successively with anaqueous solution of sodium bicarbonate and water and dried over sodiumsulfate. After distilling off the solvent under reduced pressure, theresidue was purified by silica gel column chromatography (eluted withdichloromethane/methanol) to thereby give 115 mg of the title compoundas yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 1.49-1.72(m, 4H), 1.79-1.91(m, 2H), 2.08-2.28(m,1H), 2.74-2.85(m, 2H), 3.25(s, 2H), 6.68(d, J=7.6 Hz, 1H), 6.73(s, 1H),6.82(d, J=7.6 Hz, 1H), 7.59-7.65(m, 2H), 8.10-8.30(br.s, 1H),8.40-8.70(br.s, 1H), 9.45(s, 1H)

MS: FAB(+)365(M⁺), 366(MH⁺)

Example 5024-[1-(10-(Methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)piperidin-4-yl]butyronitrile

The title compound was obtained as yellow crystals by treating4-[1-(tert-butoxycarbonyl) piperidin-4-yl]butyronitrile and8-chloromethyl-10H-pyrazino[2,3-b][1,4]benzothiazine by the same methodas the one of Example 66.

¹H-NMR(CDCl₃) δ ppm: 1.40(m, 2H), 1.65(m, 7H), 1.96(t, J=10 Hz, 2H),2.34(t, J=7 Hz, 2H), 2.87(t, J=10 Hz, 2H), 3.43(s, 2H), 3.55(s, 3H),5.31(s, 2H), 6.94(d, J=8 Hz, 1H), 6.96(d, J=8 Hz, 1H), 7.10(s, 1H),7.83(d, J=3 Hz, 1H), 7.84(d, J=3 Hz, 1H)

Example 5031-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-4-[2-(tetrazol-5-yl)ethyl]piperidine

To a solution of 0.323 g of4-[1-(10-methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)piperidin-4-yl]butyronitrilein 1-methyl-2-pyrrolidone (10 ml) were added in a nitrogen atmosphere0.354 g of sodium azide and 0.376 g of ammonium chloride. Next, theresulting mixture was stirred under heating to 150° C. for 28 hours.After distilling off the solvent under reduced pressure, the residue waspurified by high-porous gel chromatography (CHP20P, 75-150μ;manufactured by Mitsubishi Chemical Industries) (eluted withmethanol/water) to thereby give 0.208 g of the title compound as paleyellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 1.10(m, 2H), 1.20(m, 1H), 1.59(br.d, J=11 Hz,2H), 1.67(quint, J=6 Hz, 2H), 1.99(t, J=11 Hz, 2H), 2.76(br.d, J=11 Hz,2H), 2.81(t, J=9 Hz, 2H), 3.27(s, 2H), 6.68(dd, J=2, 8 Hz, 1H), 6.74(d,J=2 Hz, 1H), 6.83(d, J=8 Hz, 1H), 7.62(d, J=3 Hz, 1H), 7.63(d, J=3 Hz,1H), 9.44(s, 1H)

MS: FAB(+)409(MH⁺)

m.p.: 149-152° C.

Example 504N-[1-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-piperidin-4-yl]-5-methyl-1,2-oxazole-4-carboxamide

50 ml of a solution of 5.7 g of 4-amino-1-benzyl-piperidine in toluenewas stirred and 2.5 ml of diketene was carefully dropped thereinto.After the completion of the reaction, the solvent was distilled offunder reduced pressure and the residue was allowed to stand at a lowtemperature. To the crystals thus precipitated was added diethylether/isopropyl ether followed by grinding and filtration. Thus 4.95 gof N-(1-benzylpiperidin-4-yl)-3-oxobutanamide was obtained as colorlesscrystals. Next, this compound was dissolved in a solvent mixture oftetrahydrofuran (25 ml) with methanol (25 ml). After adding 1.0 g of 10%palladium-carbon, the resulting mixture was stirred under atmosphericpressure in a hydrogen atmosphere for 2 hours. After filtering offinorganic matters through celite, the solvent was distilled off underreduced pressure. The oily residue thus obtained was dissolved in 50 mlof N,N-dimethylformamide and 4.1 g of8-chloromethyl-10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazineand 2.1 g of potassium carbonate were added thereto. The resultingmixture was heated to 100° C. for 1 hour. Then the reaction mixture wasbrought back to room temperature and distributed into water and ethylacetate. The organic layer was extracted, washed with water and driedover sodium sulfate. After distilling off the solvent under reducedpressure, the residue was purified by silica gel column chromatography(eluted with dichloromethane/methanol) to thereby give 3.7 g ofN-[1-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-piperidin-4-yl]-3-oxobutanamideas yellow crystals. Further, 3.7 g of thisN-[1-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-piperidin-4-yl]-3-oxobutanamidewas dissolved in toluene (10 ml). After adding 1.3 ml ofN,N-dimethylformamide dimethyl acetal, the mixture was heated to 90° C.for 30 minutes. After distilling off the solvent under reduced pressure,10 ml of methanol and 800 mg of hydroxylamine hydrochloride were addedto the yellow oily residue thus obtained. Then the resulting mixture washeated under reflux for 30 minutes. The reaction mixture was broughtback to room temperature and distributed into water and ethyl acetate.The organic layer was extracted, washed with water and dried over sodiumsulfate. After distilling off the solvent under reduced pressure, 30 mlof glacial acetic acid was added to the yellow oily residue thusobtained. Then the resulting mixture was heated to 80° C. for 4 hours.After distilling off the solvent under reduced pressure, the residue waspurified by silica gel column chromatography (eluted withdichloromethane/methanol) and recrystallized from diethyl ether/ethylacetate to thereby give 1.6 g of the title compound as yellow crystals.

¹H-NMR(CDCl₃) δ ppm: 1.45-1.57(m, 2H), 1.94-2.02(m, 2H), 2.07-2.17(m,2H), 2.70(s, 3H), 2.78-2.87(m, 2H), 3.34(s, 2H), 3.88-4.00(m, 1H),5.66(br.d, J=7.6 Hz, 1H), 6.53(d, J=1.3 Hz, 1H), 6.68-6.72(br.s, 1H),6.75(dd, J=1.3, 7.6 Hz, 1H), 6.82(d, J=7.9 Hz, 1H), 7.57(d, J=3.0 Hz,1H), 7.69(d, J=3.0 Hz, 1H), 8.36(s, 1H)

MS: FAB(+)423(MH⁺)

Example 505N-[1-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-piperidin-4-yl]-3-oxo-2-cyanobutanamide

To 10 ml of a solution of 500 mg ofN-[1-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-piperidin-4-yl]-5-methyl-1,2-oxazole-4-carboxamidein tetrahydrofuran was added 400 μl of N,N-dimethylformamide dimethylacetal and the resulting mixture was heated under reflux for 4 hours.After distributing into water and ethyl acetate, the aqueous layer wasextracted and washed with diethyl ether. After distilling off theorganic solvent contained therein under reduced pressure, the residuewas acidified with dilute hydrochloric acid and purified by high-porousgel chromatography (CHP20P, 75-150μ; manufactured by Mitsubishi ChemicalIndustries) (eluted with methanol/water) to thereby give 110 mg of thetitle compound as pale yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 1.38-1.54(m, 2H), 1.77-2.04(m, 4H), 1.99(br.s,3H), 2.87-3.07(m, 2H), 3.32(s, 2H), 4.01-4.10(m, 1H), 6.76(s, 1H),6.77(br.d, J=7.7 Hz, 1H), 7.00(d, J=7.7 Hz, 1H), 7.66(s, 2H),9.48-9.59(m, 1H), 9.70(br.s, 1H)

MS: FAB(+)423(MH⁺)

Examples 506 and 507

Starting with known compounds, the following compounds were obtained bythe same method as the one of Example 63.

Ex. Structural formula NMR 506

¹H-NMR (CDCl₃) δ ppm: 1.25(t, J=7Hz, 3H), 1.7-1.82(m, 2H), 1.83- 1.93(m,2H), 1.95-2.05(m, 2H), 2.2- 2.35(m, 1H), 2.8-2.9(m, 2H), 3.36(s, 2H),3.46(s, 3H), 4.13(q, J=7Hz, 2H), 5.31(s, 2H), 6.78(s, 2H), 6.88(s, 1H),7.41(d, J=3Hz, 1H), 7.57(d, J=3Hz, 1H) 507

¹H-NMR (CDCl₃) δ ppm: 1.23(t, J=6Hz, 3H), 1.38-1.62(m, 2H), 1.65-1.76(m, 1H), 1.86-1.96(m, 1H), 1.96- 2.10(m, 1H), 2.10-2.30(m, 1H),2.50- 2.60(m, 1H), 2.65-2.70(m, 1H), 2.90- 2.97(m, 1H), 3.41(d, J=14Hz,1H), 3.45(d, J=14Hz, 1H), 3.54(s, 3H), 4.10(q, J=6Hz, 2H), 5.28(s, 2H),6.92(d, J=8Hz, 1H), 6.94(d, J=8Hz, 1H), 7.10(s, 1H), 7.82(s, 2H)

Example 508 Ethyl4-[1-(10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)piperidin-4-yl]-2-butenoate

The title compound was obtained as yellow crystals by the same method asthe one of Example 66.

¹H-NMR(CDCl₃) δ ppm: 1.24(t, J=6 Hz, 3H), 1.36-1.46(m, 1H), 1.64-1.70(m,2H), 1.76(br.s, 2H), 1.89-1.94(m, 2H), 2.14(t, J=6 Hz, 2H), 2.80-2.90(m,2H), 3.39(s, 2H), 3.54(s, 3H), 4.16(q, J=6 Hz, 2H), 5.26(s, 2H), 5.80(d,J=16 Hz, 1H), 6.90(dt, J=6, 16 Hz, 1H), 6.94(d, J=8 Hz, 1H), 6.96(d, J=8Hz, 1H), 7.08(s, 1H), 7.81(s, 2H)

Examples 509 to 516

The following compounds were obtained by the same method as the one ofExample 508.

Ex. Structural formula NMR 509

¹H-NMR (CDCl₃) δ ppm: 1.25(t, J=7.2Hz, 3H), 1.36-1.51(m, 2H), 1.87-1.95(m, 2H), 2.00- 2.12(m, 2H), 2.46- 2.58(m, 3H), 2.66- 2.74(m, 2H),2.85- 2.93(m, 2H), 3.54(s, 3H), 3.76(s, 2H), 4.13(q, J=7.2Hz, 2H),5.29(s, 2H), 6.94(d, J=7.4Hz, 1H), 6.97(d, J=7.4Hz, 1H), 7.13(s, 1H),7.83(s, 2H) 510

¹H-NMR (CDCl₃) δ ppm: 1.25(t, J=7.2Hz, 3H), 1.43-1.58(m, 2H), 1.69-1.78(m, 2H), 1.85-1.94(m, 2H), 1.94- 2.03(m, 2H), 2.30- 2.38(m, 3H),2.41- 2.53(m, 2H), 2.93-3.03(m, 2H), 3.55(s, 3H), 3.76(s, 2H), 4.13(q,J=7.2Hz, 2H), 5.29(s, 2H), 6.93(d, J=8.0Hz, 1H), 6.96(d, J=8.0Hz, 1H),7.12(s, 1H), 7.83(s, 2H) 511

¹H-NMR (CDCl₃) δ ppm: 1.26(t, J=7Hz, 3H), 1.42-1.60(m, 2H), 1.84-1.94(m, 2H), 2.16-2.26(m, 2H), 2.44- 2.56(m, 1H), 2.84-2.94(m, 2H),3.20(s, 2H), 3.53(s, 3H), 3.76(s, 2H), 4.17(q, J=7Hz, 2H), 5.30(s, 2H),6.90-7.00(m, 2H), 7.13(s, 1H), 7.80-7.85(m, 2H) 512

¹H-NMR (CDCl₃) δ ppm: 1.28(t, J=6.8Hz, 3H), 1.33-1.43(m, 2H), 1.89-1.97(m, 2H), 2.72-2.81(m, 1H), 2.81- 2.89(m, 1H), 3.07-3.15(m, 1H),3.46(s, 2H), 3.53(s, 3H), 3.69-3.79(m, 1H), 3.77(s, 2H), 4.20(q,J=6.8Hz, 2H), 4.37-4.44(m, 1H), 5.29(s, 2H), 6.94(d, J=7.6Hz, 1H),6.97(d, J=7.6Hz, 1H), 7.13(s, 1H), 7.83(d, J=2.8Hz, 1H), 7.84(d,J=2.8Hz, 1H) 513

¹H-NMR (CDCl₃) δ ppm: 1.30-1.47(m, 2H), 1.36(t, J=7.0Hz, 3H),1.90-2.00(m, 2H), 2.77-2.85(m, 1H), 2.92- 3.00(m, 1H), 3.08-3.17(m, 1H),3.53(s, 3H), 3.63-3.71(m, 1H), 3.78(s, 2H), 4.24- 4.34(m, 1H), 4.32(q,J=7.0Hz, 2H), 5.29(s, 2H), 6.93(dd, J=1.4, 7.6Hz, 1H), 6.97(d, J=7.6Hz,1H), 7.13(d, J=1.4Hz, 1H), 7.83(d, J=2.6Hz, 1H), 7.84(d, J=2.6Hz, 1H)514

¹H-NMR (CDCl₃) δ ppm: 1.28(t, J=7.2Hz, 3H), 1.52-1.72(m, 4H), 1.91-2.03(m, 3H), 2.15(s, 3H), 2.91-2.97(m, 2H), 3.44(s, 2H), 3.54(s, 3H),4.14(q, J=7.2Hz, 2H), 5.29(s, 2H), 5.68(s, 1H), 6.94(d, J=8.5Hz, 1H),6.97(d, J=8.5Hz, 1H), 7.11(s, 1H), 7.84(s, 2H) 515

¹H-NMR (CDCl₃) δ ppm: 1.30-1.47(m, 2H), 1.36(t, J=7.0Hz, 3H),1.90-2.00(m, 2H), 2.77-2.85(m, 1H), 2.92- 3.00(m, 1H), 3.08-3.17(m, 1H),3.53(s, 3H), 3.63-3.71(m, 1H), 3.78(s, 2H), 4.24- 4.34(m, 1H), 4.32(q,J=7.0Hz, 2H), 5.29(s, 2H), 6.93(dd, J=1.4, 7.6Hz, 1H), 6.97(d, J=7.6Hz,1H), 7.13(d, J=1.4Hz, 1H), 7.83(d, J=2.6Hz, 1H), 7.84(d, J=2.6Hz, 1H)516

¹H-NMR (CDCl₃) δ ppm: 0.91(d, J=6.8Hz, 3H), 1.13-1.40(m, 3H), 1.25(t,J=7.2Hz, 3H), 1.54-1.63(m, 2H), 1.85- 1.96(m, 3H), 2.08(dd, J=8.4,14.8Hz, 1H), 2.38(dd, J=4.9, 14.8Hz, 1H), 2.81-2.94(m, 2H), 3.42(s, 2H),3.54(s, 3H), 4.12(q, J=7.2Hz, 2H), 5.29(s, 2H), 6.93(d, J=7.9Hz, 1H),6.96(d, J=7.9Hz, 1H), 7.10(br.s, 1H), 7.83(s, 2H)

Examples 517 and 518

The following compounds were obtained as yellow crystals by the samemethod as the one of Example 66 by using trifluoroacetic acid as asubstitute for hydrochloric acid.

Ex. Structural formula NMR 517

¹H-NMR(CDCl₃)δppm: 1.13(d, J=7Hz, 3H), 1.25(t, J=7Hz, 3H), 1.1-1.45(m,7H), 1.55- 1.70(m, 2H), 1.65- 1.80(m, 2H), 1.85- 1.95(m, 2H), 2.35-2.45(m, 1H), 2.85(br.d, J=12Hz, 2H), 3.43(s, 2H), 3.55(s, 3H), 4.12(q,J=7Hz, 2H), 5.36(s, 2H), 6.80(dd, J=5, 8Hz, 1H), 6.92(dd, # J=2, 8Hz,1H), 6.97(d, J=8Hz, 1H), 7.11(d, J=2Hz, 1H), 7.28(dd, J=2, 8Hz, 1H),8.05(dd, J=2, 5Hz, 1H) 518

¹H-NMR(CDCl₃)δppm: 1.10-1.30(m, 5H), 1.14(s, 6H), 1.26(t, J=6Hz, 3H),1.48- 1.56(m, 2H), 1.58- 1.70(m, 2H), 1.84- 1.96(m, 2H), 2.80- 2.90(m,2H), 3.40(s, 2H), 3.52(s, 3H), 4.09(q, J=6Hz, 2H), 5.29(s, 2H), 6.93(d,J=8Hz, 1H), 6.96(d, J=8Hz, 1H), 7.09(s, # 1H), 7.82(s, 2H)

Examples 519 to 521

The following compounds were obtained by the same method as the one ofExample 64 by using anhydrous potassium carbonate as a substitute forN,N-diisopropylamine.

Ex. Structural formula NMR 519

¹H-NMR(CDCl₃)δppm: 1.87-2.0(m, 2H), 2.16(br.t, J=12Hz, 2H), 2.53(br.d,J=12Hz, 2H), 2.75-2.85(m, 2H), 3.39(s, 2H), 3.52(s, 3H), 3.64(s, 3H),3.79(s, 3H), 5.27(s, 2H), 6.85(d, J=9Hz, 2H), 6.9-6.96(m, 1H), 6.95(d,J=8Hz, 1H), 7.11(s, 1H), 7.29(d, J=9Hz, 2H), # 7.82(d, J=3Hz, 1H),7.83(d, J=3Hz, 1H) 520

¹H-NMR(CDCl₃)δppm: 1.88-2.0(m, 2H), 2.15(br.t, J=12Hz, 2H), 2.53(br.d,J=12Hz, 2H), 2.75-2.84(m, 2H), 3.39(s, 2H), 3.47(s, 3H), 3.52(s, 3H),3.64(s, 3H), 5.15(s, 2H), 5.27(s, 2H), 6.9- 6.96(m, 1H), 6.95(d, J=8Hz,1H), 6.98(d, # J=9Hz, 2H), 7.10(s, 1H), 7.29(d, J=9Hz, 2H), 7.82(d,J=3Hz, 1H), 7.83(d, J=3Hz, 1H) 521

¹H-NMR(CDCl₃)δppm: 1.22-1.35(m, 2H), 1.36(t, J=6Hz, 3H), 1.42-1.60(m,3H), 1.83- 1.93(m, 2H), 2.58(d, J=6Hz, 2H), 2.80-2.90(m, 2H), 3.40(s,2H), 3.52(s, 3H), 4.36(q, J=6Hz, 2H), 5.29(s, 2H), 6.92(d, J=8Hz, 1H),6.94(d, J=8Hz, 1H), # 7.09(s, 1H), 7.19(d, J=9Hz, 2H), 7.82(s, 2H),7.94(d, J=9Hz, 2H)

Example 522Methyl[1-(10-methoxymethyl)-10H-pyrazino[2,3-b][1,4]-benzothiazin-8-ylmethyl]-4-phenylpiperidin-4-yl]carboxylate

To a solution of 0.46 g ofmethyl[(1-benzyl-4-phenylpiperidin)-4-yl]carboxylate in1,2-dichloroethane (10 ml) was added 0.18 ml of 1-chloroethylchloroformate at 0° C. After stirring for 15 minutes, the resultingmixture was heated under reflux for additional 1 hour. After distillingoff the solvent under reduced pressure, 50 ml of methanol was added tothe residue and the resulting mixture was heated under reflux for 1hour. After distilling off the solvent under reduced pressure, 0.4 g ofmethyl(4-phenylpiperidin-4-yl)carboxylate was obtained as colorlesscrystals. 0.4 g of these crystals were dissolved in 20 ml ofN,N-dimethylformamide and 0.44 g of8-(chloromethyl)-10H-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazineand 0.62 g of anhydrous potassium carbonate were added thereto. Afterreacting at 60° C. for 1 hour, water was added to the reaction mixture.The mixture was extracted with ethyl acetate, washed with a saturatedaqueous solution of sodium chloride and dried over anhydrous magnesiumsulfate. After distilling off the solvent under reduced pressure, theresidue was purified by silica gel column chromatography (eluted withn-hexane/ethyl acetate) to thereby give 0.55 g of the title compound asa yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.9-2.05(m, 2H), 2.1-2.25(m, 2H), 2.5-2.6(m, 2H),2.75-2.85(m, 2H), 3.41(m, 2H), 3.52(s, 3H), 3.65(s, 3H), 5.28(s, 2H),6.92-6.96(m, 1H), 6.95(s, 1H), 7.10-7.13(m, 1H), 7.2-7.4(m, 5H), 7.82(d,J=3 Hz, 1H), 7.83(d, J=3 Hz, 1H)

Examples 523 to 525

The following compounds were obtained by the same method as the one ofExample 522.

Ex. Structural formula NMR 523

¹H-NMR(CDCl₃)δppm: 1.26(t, J=7Hz, 3H), 2.4-2.5(m, 4H), 2.5- 2.58(m, 6H),2.58- 2.66(m, 2H), 3.46(s, 2H), 3.53(s, 3H), 4.13(q, J=7Hz, 2H), 5.29(s,2H), 6.90- 6.96(m, 1H), 6.97(d, J=8Hz, 1H), 7.12(s, 1H), 7.83(d, J=3Hz,1H), 7.84(d, J=3Hz, 1H) 524

¹H-NMR(CDCl₃)δppm: 1.17(s, 6H), 1.38- 1.56(m, 4H), 2.30(m, 2H),2.39-2.54(br.s, 8H), 3.44(s, 2H), 3.53(s, 3H), 3.65(s, 3H), 5.26(s, 2H),6.94(s, 2H), 7.10(s, 1H), 7.82(m, 2H) 525

NMR(CDCl₃) 1.29(t, J=6.8Hz, 3H), 1.56-1.70(m, 2H), 1.77- 1.85(m, 2H),2.02- 2.11(m, 2H), 2.87- 2.98(m, 2H), 3.10(s, 3H), 3.42(br.s, 2H),3.54(s, 3H), 3.58- 3.69(m, 1H), 4.06(s, 2H), 4.18(q, J=6.8Hz, 2H),5.29(s, 2H), # 6.92(dd, J=1.2, 7.6Hz, 1H), 6.97(d, J=7.6Hz, 1H),7.07(br.d, J=1.2Hz, 1H), 7.84(d, J=2.8Hz, 1H), 7.85(d, J=2.8Hz, 1H)

Example 526 Ethyl4-[1-(10-methoxymethyl)-10H-pyrazino[2,3-b][1,4]-benzothiazin-8-ylmethyl]piperidin-4-yl]-2-methylbutanoate

To a solution of 15.7 g of ethyl4-[1-benzyloxycarbonyl]piperidin-4-yl]-2-methyl-2-butenoate in ethanol(200 ml) was added 3.1 g of 10% palladium-carbon (moisture content: 50%)and hydrogenation reaction was effected at ordinary temperature underatmospheric pressure for 8 hours and 40 minutes. After filtering off thepalladium-carbon, the solvent was concentrated under reduced pressure tothereby give 10.06 g of crude ethyl4-(piperidin-4-yl)-2-methyl-2-butanoate as a pale yellow oily substance.A 3.74 g portion of this product was dissolved in 50 ml ofN,N-dimethylformamide. After adding 4.06 g of8-(chloromethyl)-10H-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazineand 20 ml of pyridine, the resulting mixture was reacted at 70° C. for11 hours. After adding water, the reaction mixture was extracted withethyl acetate, washed with a saturated aqueous solution of sodiumchloride and dried over anhydrous magnesium sulfate. After distillingoff the solvent under reduced pressure, the residue was purified bysilica gel column chromatography (eluted with toluene/ethyl acetate) tothereby give 4.5 g of the title compound as a yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.07(d, J=7 Hz, 3H), 1.10-1.30(m, 4H), 1.13(t, J=6Hz, 3H), 1.58-1.70(m, 3H), 1.70-1.82(m, 2H), 1.88-1.98(m, 2H),2.32-2.41(m, 1H), 2.80-2.88(m, 2H), 3.42(s, 2H), 3.52(s, 3H), 4.11(q,J=6 Hz, 2H), 5.30(s, 2H), 6.90(d, J=8 Hz, 1H), 6.92(d, J=8 Hz, 1H),7.09(s, 1H), 7.82(s, 2H)

Examples 527 to 530

The following compounds were obtained by the same method as the one ofExample 526.

Ex. Structural formula NMR 527

¹H-NMR(CDCl₃)δppm: 1.13(d, J=7Hz, 3H), 1.1- 1.3(m, 3H), 1.24(t, J=7Hz,3H), 1.3-1.5(m, 1H), 1.6-1.7(m, 3H), 1.7-1.85(m, 2H), 1.85- 1.95(m, 2H),2.3-2.43(m, 1H), 2.83(br.d, J=9Hz, 2H), 3.35(s, 2H), 3.45(s, 3H),4.11(q, J=7Hz, 2H), 5.29(m, 2H), # 6.77(s, 2H), 6.87(s, 1H), 7.40(d,J=3Hz, 1H), 7.55(d, J=3Hz, 1H) 528

¹H-NMR(CDCl₃)δppm: 1.13(d, J=7Hz, 3H), 1.21(m, 4H), 1.24(t, J=7Hz, 3H),1.41(m, 1H), 1.65(m, 4H), 1.92(t, J=11Hz, 2H), 2.37(sext, J=7Hz, 1H),2.83(d, J=11Hz, 2H), 3.42(s, 2H), 3.53(s, 3H), 4.12(q, J=7Hz, 2H),5.03(s, 2H), 6.87(d, J=6Hz, 1H), 6.96(dd, # J=2, 8Hz, 1H), 7.02(d,J=2Hz, 1H), 7.04(d, J=8Hz, 1H), 8.18(s, 1H), 8.26(d, J=6Hz, 1H) 529

¹H-NMR(CDCl₃)δppm: 1.26(t, J=8Hz, 3H), 1.42-1.60(m, 2H), 1.84- 1.94(m,2H), 2.16- 2.26(m, 2H), 2.44- 2.56(m, 1H), 2.84- 2.94(m, 2H), 3.20(s,2H), 3.53(br.s, 3H), 3.76(s, 2H), 4.17(q, J=8Hz, 2H), 5.2-5.35(m, 3H),6.9-7.0(m, 2H), 7.13(s, 1H), 7.8-7.85(m, # 2H) 530

¹H-NMR(CDCl₃)δppm: 1.13(d, J=6.8Hz, 3H), 1.15-1.30(m, 5H), 1.25(t,J=7.2Hz, 3H), 1.35-1.47(m, 1H), 1.57- 1.69(m, 3H), 1.88- 1.98(m, 2H),2.33- 2.42(m, 1H), 2.79- 2.86(m, 2H), 3.40(s, 2H), 3.52(s, 3H), 4.12(q,J=6.8Hz, 2H), 5.26(s, 2H), 7.28(br.d, # J=1.6Hz, 1H), 7.80(d, J=2.8Hz,1H), 7.84(d, J=2.8Hz, 1H), 7.95(d, J=1.6Hz, 1H)

Example 531 Ethyl[4-1-[10-(methoxymethyl)-7-methoxy-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]piperidin-4-yl]-2-methyl-butanoate

To a solution of 0.7 g of7-methoxy-10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine-8-carboxaldehydeand 0.98 g of ethyl 4-(piperidin-4-yl)-2-methylbutanoate in acetonitrile(50 ml) was added 0.29 g of sodium cyanoborohydride. After stirring atroom temperature for 10 minutes, 0.4 ml of acetic acid was droppedthereinto and the resulting mixture was reacted for 12 hours. Afteradding water, the reaction mixture was extracted with ethyl acetate,washed with a saturated aqueous solution of sodium chloride and driedover anhydrous magnesium sulfate. After distilling off the solvent underreduced pressure, the residue was purified by silica gel columnchromatography (eluted with n-hexane/ethyl acetate) to thereby give 0.2g of the title compound as a pale yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.15(d, J=7 Hz, 3H), 1.26(t, J=7 Hz, 3H),1.2-1.3(m, 2H), 1.35-1.50(m, 3H), 1.55-1.80(m, 6H), 2.2-2.40(m, 2H),2.3-2.43(m, 1H), 3.0-3.15(m, 2H), 3.56(s, 3H), 3.79(s, 3H), 4.13(q, J=7Hz, 2H), 5.28(s, 2H), 6.55(s, 1H), 7.26(s, 1H), 7.83(d, J=3 Hz, 1H),7.85(d, J=3 Hz, 1H)

Example 532 10H-Pyrazino[2,3-b][1,4]benzothiazine-8-carboxylic acid

To 50 ml of a solution of 2 g of methyl10H-pyrazino[2,3-b][1,4]benzothiazine-8-carboxylate in methanol wasadded 0.8 g of sodium hydroxide and the resulting mixture was heatedunder reflux for 1 hour. After distilling off the methanol under reducedpressure, a 1 N aqueous solution of hydrochloric acid was added theretoso as to adjust the pH value to 5 to 6. Then the mixture was extractedwith ethyl acetate/dichloromethane and the organic layer was dried overanhydrous magnesium sulfate. After distilling off the solvent underreduced pressure, 1.9 g of the title compound was obtained as a yellowsolid.

¹H-NMR(DMSO-d₆) δ ppm: 3.40(s, 3H), 5.26(s, 2H), 7.22(d, J=8.1 Hz, 1H),7.52(dd, J=1.7, 8.1 Hz, 1H), 7.64(d, J=1.7 Hz, 1H), 7.94(d, J=2.6 Hz,1H), 7.87(d, J=2.6 Hz, 1H), 13.05-13.25(br.s, 1H)

Example 533 Ethyl4-[1-[(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbonyl]piperidin-4-yl]-2-methylbutanoate

To a solution of 1 g of10H-pyrazino[2,3-b][1,4]-benzothiazine-8-carboxylic acid intetrahydrofuran (50 ml) were added under ice-cooling 0.6 ml oftriethylamine and 0.55 ml of diethyl chlorophosphate. The resultingmixture was reacted at room temperature for 0.5 hour. Next, 0.66 g ofethyl 4-(piperidin-4-yl)-2-methylbutanoate was added thereto and theresulting mixture was stirred at room temperature for 12 hours. Afteradding ethyl acetate to the reaction mixture, the organic layer waswashed with water and dried over anhydrous magnesium sulfate. Afterdistilling off the solvent under reduced pressure, the residue waspurified by silica gel column chromatography (eluted with n-hexane/ethylacetate) to thereby give 1.0 g of the title compound as a yellow oilysubstance.

¹H-NMR(CDCl₃) δ ppm: 1.0-1.8(m, 9H), 1.15(d, J=7 Hz, 3H), 1.26(t, J=7Hz, 3H), 2.3-2.45(m, 1H), 2.6-2.7(m, 1H), 2.9-3.3(m, 1H), 3.51(s, 3H),3.6-3.8(m, 1H), 3.95-4.10(m, 1H), 4.13(q, J=7 Hz, 2H), 5.26(s, 2H),6.99(dd, J=2, 8 Hz, 1H), 7.04(d, J=8 Hz, 1H), 7.18(d, J=2 Hz, 1H),7.85(d, J=3 Hz, IH), 7.87(d, J=3 Hz, 1H)

Example 534 10H-Pyrazino[2,3-b][1,4]benzothiazine-8-acetonitrile

To 50 ml of a solution of 5 g of8-(chloromethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine in dimethylsulfoxide was added 0.92 g of sodium cyanide and the resulting mixturewas reacted at 60° C. for 1 hour. After adding ethyl acetate, theorganic layer was washed with water and dried over anhydrous magnesiumsulfate. After distilling off the solvent under reduced pressure, 4.7 gof the title compound was obtained as a yellow solid.

¹H-NMR(DMSO-d₆) δ ppm: 3.38(s, 3H), 4.00(s, 2H), 5.24(s, 2H), 6.99(dd,J=1.8, 8.0 Hz, 1H), 7.09(d, J=1.8 Hz, 1H), 7.15(d, J=8.0 Hz, 1H),7.94(d, J=2.4 Hz, 1H), 7.97(d, J=2.4 Hz, 1H)

Example 535 10H-Pyrazino[2,3-b][1,4]benzothiazine-8-acetic acid

4.7 g of 10H-pyrazino[2,3-b][1,4]benzothiazine-8-acetonitrile wasdissolved in 100 ml of ethanol. After adding 2.8 g of potassiumhydroxide, the resulting mixture was heated under reflux for 16 hours.After distilling off the ethanol, water was added and the mixture wasmade weakly acidic with dilute hydrochloric acid followed by theextraction with ethyl acetate and dichloromethane. The organic layer wasdried over anhydrous magnesium sulfate. After distilling off the solventunder reduced pressure, 3.85 g of the title compound was obtained asyellow crystals.

¹H-NMR(CDCl₃) δ ppm: 3.53(s, 3H), 3.60(s, 2H), 5.27(s, 2H), 6.90(dd,J=2, 8 Hz, 1H), 6.98(d, J=8 Hz, 1H), 7.08(d, J=2 Hz, 1H), 7.83(d, J=3Hz, 1H), 7.85(d, J=3 Hz, 1H)

Example 536 Ethyl4-[1-[(10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]carbamoyl]piperidin-4-yl]-2-methylbutanoate

To a solution of 0.7 g of 10H-pyrazino[2,3-b][1,4]benzothiazine-8-aceticacid in tetrahydrofuran (50 ml) were added 0.35 ml of triethylamine and0.55 ml of diphenyl phosphate azide and the resulting mixture wasstirred at room temperature for 3 hours. Next, it was heated underreflux for 1.5 hours. After adding 0.55 g of ethyl4-(piperidin-4-yl)-2-methylbutanoate, the resulting mixture was reactedat room temperature for 1 hour. After adding ethyl acetate, the reactionmixture was washed with water and dried over anhydrous magnesiumsulfate. After distilling off the solvent under reduced pressure, theresidue was purified by silica gel column chromatography (eluted withdichloromethane/methanol) to thereby give 0.66 g of the title compoundas a yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.14(d, J=7 Hz, 3H), 1.1-1.2(m, 1H), 1.25(t, J=7Hz, 3H), 1.25-1.35(m, 2H), 1.3-1.5(m, 2H), 1.6-1.75(m, 4H), 2.3-2.45(m,1H), 2.7-2.8(m, 2H), 3.52(s, 3H), 3.85-3.95(m, 2H), 4.12(q, J=7 Hz, 2H),4.35(d, J=6 Hz, 2H), 4.73(br.t, J=6 Hz, 1H), 5.26(s, 2H), 6.91(dd, J=1,8 Hz, 1H), 6.96(d, J=8 Hz, 1H), 7.08(d, J=1 Hz, 1H), 7.8-7.86(m, 2H)

Example 537 Ethyl1-[(10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]-benzothiazin-8-ylmethyl]-2,3-dehydro-3-piperidinecarboxylate

To a solution of 0.506 g of diisopropylamine in tetrahydrofuran (10 ml)was added in a nitrogen atmosphere at 0° C. 3.14 ml of a 1.6 M solutionof n-butyllithium in hexane. Further, a solution of 0.776 g of ethyl2,3-dehydro-3-piperidinecarboxylate in tetrahydrofuran (2 ml) was addedthereto to thereby prepare a lithium salt. In another container, 1.00 gof8-(chloromethyl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazinewas added to a solution of 1.53 g of sodium iodide inN,N-dimethylformamide (10 ml). After heating for 2 hours, the mixturewas brought back to room temperature. The solution thus obtained wasadded to the solution of the lithium salt as described above and theresulting mixture was stirred at room temperature for 2 hours. Afterconcentrating under reduced pressure, the residue was dissolved in ethylacetate and water. The organic layer was concentrated and the residuewas purified by silica gel column chromatography (eluted withdichloromethane/methanol) to thereby give 0.375 g of the title compoundas pale yellow crystals.

¹H-NMR(CDCl₃) δ ppm: 1.26(t, J=7 Hz, 3H), 1.52(quint, J=6 Hz, 2H),2.29(t, J=6 Hz, 2H), 2.98(t, J=6 Hz, 2H), 3.49(s, 3H), 4.15(q, J=7 Hz,2H), 4.23(s, 2H), 5.22(s, 2H), 6.82(dd, J=2, 7 Hz, 1H), 6.97(d, J=2 Hz,1H), 6.98(d, J=1, 7 Hz, 1H), 7.51(s, 1H), 7.83(d, J=3 Hz, 1H), 7.84(d,J=3 Hz, 1H)

Example 5381-[10-(Methoxymethyl)-10H-pyrazino[2,3-b][1,4]-benzothiazin-8-ylmethyl]-3-(tert-butyldimethylsilyloxymethyl)pyridiniumchloride

¹H-NMR(DMSO-d₆) δ ppm: 0.00(s, 6H), 0.75(s, 9H), 3.35(s, 3H), 4.84(s,2H), 5.20(s, 2H), 5.75(s, 2H), 7.05(dd, J=2, 8 Hz, 1H), 7.16(d, J=8 Hz,1H), 7.18(d, J=2 Hz, 1H), 7.88(d, J=3 Hz, 1H), 7.94(d, J=3 Hz, 1H),8.20(t, J=7 Hz, 1H), 8.44(d, J=7 Hz, 1H), 8.80(s, 1H), 9.06(d, J=7 Hz,1H)

Example 5391-[10-(Methoxymethyl)-10H-pyrazino[2,3-b][1,4]-benzothiazin-8-ylmethyl]-3,4-dehydro-3-(tert-butyldimethylsilyloxymethyl)piperidine

To a solution of 0.326 g of1-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-3-(tert-butyldimethylsilyloxymethyl)pyridiniumchloride in methanol (10 ml) was added at room temperature in a nitrogenatmosphere 0.06 g of sodium borohydride. After stirring for 18 hours,water and ethyl acetate were added thereto. The organic layer was driedover anhydrous magnesium sulfate, filtered and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluted with n-hexane/ethyl acetate) to thereby give0.176 g of the title compound as pale yellow crystals.

¹H-NMR(CDCl₃) δ ppm: 0.05(s, 6H), 0.83(s, 9H), 2.10-2.15(m, 2H), 2.46(t,J=6 Hz, 2H), 2.86(br.s, 2H), 3.41(s, 3H), 3.49(s, 2H), 3.90(br.s, 2H),5.25(s, 2H), 5.65(m, 1H), 6.92(d, J=8 Hz, 1H), 6.95(dd, J=2, 8 Hz, 1H),7.08(d, J=8 Hz, 1H), 7.79(d, J=3 Hz, 1H), 7.80(d, J=3 Hz, 1H)

Example 5401-[10-(Methoxymethyl)-10H-pyrazino[2,3-b][1,4]-benzothiazin-8-ylmethyl]-3,4-dehydro-3-piperidinemethanol

To a solution of 0.176 g of1-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]-benzothiazin-8-ylmethyl]-3,4-dehydro-3-(tert-butyldimethylsilyloxymethyl)piperidinein tetrahydrofuran (5 ml) was added at 0° C. in a nitrogen atmosphere 1ml of a 1 M solution of tetra-n-butylammonium fluoride intetrahydrofuran and the resulting mixture was stirred at roomtemperature for 3 hours. After distilling off the solvent under reducedpressure, the residue was purified by silica gel column chromatography(eluted with dichloromethane/methanol) to thereby give 0.100 g of thetitle-compound as pale yellow crystals.

¹H-NMR(CDCl₃) δ ppm: 2.18(m, 2H), 2.54(t, J=6 Hz, 2H), 3.04(br.s, 2H),3.53(s, 3H1), 3.57(s, 2H), 4.00(s, 2H), 5.30(s, 2H), 5.64(br.s, 1H),6.95(s, 2H), 7.13(s, 1H), 7.81(d, J=3 Hz, 1H), 7.83(d, J=3 Hz, 1H)

Example 5411-[10-(Methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-3,4-dehydro-3-piperidinecarbaldehyde

To a solution of 0.150 g of1-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-3,4-dehydro-3-piperidinemethanolin dichloromethane (4 ml) was added 1.00 g of manganese dioxide. Afterstirring for 3 hours, the mixture was filtered. After distilling off thesolvent under reduced pressure, 0.108 g of the title compound wasobtained as pale yellow crystals.

¹H-NMR(CDCl₃) δ ppm: 2.47(m, 2H), 2.58(t, J=7 Hz, 2H), 3.20(m, 2H),3.53(s, 3H), 3.59(s, 2H), 5.30(s, 2H), 6.86(m, 1H), 6.96(s, 2H), 7.11(s,1H), 7.83(d, J=3 Hz, 1H), 7.84(d, J=3 Hz, 1H), 9.42(s, 1H)

Example 542 Methyl1-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-3,4-dehydro-3-piperidinecarboxylate

To a solution of 0.108 g of1-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]-benzothiazin-8-ylmethyl]-3,4-dehydro-3-piperidinecarbaldehydein methanol (5 ml) were added 0.096 g of potassium cyanide, 0.504 g ofmanganese dioxide and 0.070 g of acetic acid and the resulting mixturewas stirred for 12 hours. Then the reaction mixture was filtered throughcelite and the celite was extracted with dichloromethane. The organiclayer was washed with a dilute aqueous solution of potassium hydroxideand concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (eluted with dichloromethane/methanol)to thereby give 0.080 g of the title compound as pale yellow crystals.

¹H-NMR(CDCl₃) δ ppm: 2.34(m, 2H), 2.54(t, J=7 Hz, 2H), 3.22(br.s, 2H),3.53(s, 3H), 3.58(s, 2H), 3.73(s, 3H), 5.28(s, 2H), 6.96(s, 2H), 7.01(m,1H), 7.12(s, 1H), 7.83(s, 2H)

Example 543 EthylN-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-N-(1-methanesulfonylpiperidin-4-yl)-aminoacetate

To a solution of 1.1 g ofN,N-[3-[[(10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-amino]penta-methylene]methanesulfonamidein 30 ml of N,N-dimethylformamide were added 0.42 g of anhydrouspotassium carbonate and 0.34 ml of ethyl bromoacetate. Then theresulting mixture was reacted at 60° C. for 2 hours. After adding ethylacetate, the reaction mixture was washed with water and a saturatedaqueous solution of sodium chloride and dried over anhydrous magnesiumsulfate. After distilling off the solvent under reduced pressure, theresidue was purified by silica gel column chromatography (eluted withmethanol/dichloromethane) to thereby give 0.34 g of the title compoundas a yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.25(t, J=7 Hz, 3H), 1.5-1.7(m, 2H), 1.9-2.0(m,2H), 2.6-2.7(m, 2H), 2.75(s, 3H), 2.7-2.8(m, 1H), 3.35(s, 2H), 3.53(s,3H), 3.78(s, 2H), 3.75-3.85(m, 2H), 4.13(q, J=7 Hz, 2H), 5.27(s, 2H),6.9-7.0(m, 2H), 7.20(s, 1H), 7.8-7.9(m, 2H)

Example 544 Ethyl[[4-[N-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]-benzothiazin-8-ylmethyl]-N-acetyl]amino]piperidin-1-yl]-acetate

To a solution of 1.1 g ofethyl[4-[[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]amino]-piperidin-1-yl]acetatein dichloromethane (30 ml) were added 0.4 ml of triethylamine and 0.2 mlof acetyl chloride and the resulting mixture was reacted at roomtemperature for 0.5 hour. Then the reaction mixture was washed withwater, dried over anhydrous magnesium sulfate and concentrated. Theresidue was purified by silica gel column chromatography (eluted withmethanol/dichloromethane) to thereby give 1.0 g of the title compound asa yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.2-1.3(m, 5H), 1.5-1.7(m, 2H), 1.8-1.9(m, 1H),2.2-2.3(m, 1H), 2.25(s, 3H), 2.9-3.0(m, 2H), 3.15and3.89(s, total2H),3.51(s, 3H), 4.16(q, J=7 Hz, 2H), 4.45and4.50(s, total2H), 4.40-4.60(m,1H), 5.23(m, 2H), 6.78(d, J=8 Hz, 1H), 6.85-7.00(m, 2H), 7.8-7.9(m, 2H)

Examples 545 to 551

The following compounds were obtained by the same method as the one ofExample 18.

Ex. Structural formula NMR 545

¹H-NMR(CDCl₃)δppm: 1.90-2.06(br.s, 2H), 2.06-2.16(br.s, 2H)2.38-2.43(br.s, 1H), 2.58-2.70(br.s, 2H), 3.18-3.30(br.s, 2H), 3.48(s,3H), 3.94(s, 2H), 5.28(s, 2H), 6.96(d, J=8Hz, 1H), 6.98(s, 1H), 7.02(d,J=8Hz, 1H), 7.79(d, J=3Hz, 1H), 7.80(d, # J=3Hz, 1H) 546

¹H-NMR(CDCl₃)δppm: 1.01(s, 6H), 1.38(br.s, 4), 2.44(br.s, 2H),2.31-2.50(br.s, 8H), 3.38(s, 2H), 3.51(s, 3H), 5.25(s, 2H), 6.89(d,J=8Hz, 1H), 6.91(d, J=1, 8Hz, 1H), 7.08(s, 1H), 7.81(d, J=3Hz, 1H),7.83(d, J=3Hz, 1H) 547

¹H-NMR(CD₃OD)δppm: 2.0-2.2(m, 2H), 2.4- 2.6(m, 2H), 2.8-3.0(m, 2H),3.0-3.2(m, 2H), 3.30(s, 2H), 3.51(s, 3H), 3.78(s, 3H), 5.38(s, 2H),6.78-7.0(m, 2H), 7.1-7.2(m, 2H), 7.3-7.4(m, 3H), 7.88(s, 1H), 7.93(s,1H) 548

¹H-NMR(DMSO-d₆)δppm: 1.6-1.75(m, 2H), 2.13(br.t, J=12Hz, 2H), 2.38(br.d,J=12Hz, 2H), 2.6-2.7(m, 2H), 3.34(s, 3H), 3.35(s, 2H), 3.36(s, 3H),5.13(s, 2H), 5.23(s, 2H), 6.93(d, J=9Hz, 3H), 7.04(d, J=8Hz, 1H),7.08-7.11(m, 1H), 7.28(d, J=8Hz, 2H), # 7.91(d, J−3Hz, 1H), 7.95(d,J=3Hz, 1H) 549

¹H-NMR(DMSO-d₆)δppm: 1.65-1.80(m, 2H), 2.08- 2.20(m, 2H), 2.35- 2.45(m,2H), 2.6-2.75(m, 2H), 3.36(s, 5H), 5.23(s, 2H), 6.94(d, J=8Hz, 1H),7.04(d, J=8Hz, 1H), 7.09(s, 1H), 7.20(t, J=8Hz, 1H), 7.30(t, J=8Hz, 2H),7.37(d, J=8Hz, 2H), 7.9- # 7.93(m, 1H), 7.93- 7.97(m, 1H) 550

¹H-NMR(CDCl₃)δppm: 1.50-1.80(m, 5H), 2.00- 2.30(m, 4H), 3.10-3.20(m,2H), 3.49(s, 3H), 3.64(s, 2H), 5.23(s, 2H), 6.91(d, J=8Hz, 1H), 6.94(d,J=8Hz, 1H), 7.09(s, 1H), 7.81(s, 2H) 551

¹H-NMR(CDCl₃)δppm: 1.20-1.30(m, 4H), 1.44- 1.58(m, 4H), 1.74-1.82(m,2H), 2.23-2.28(m, 3H), 2.42-2.56(m, 2H), 3.48(s, 3H), 4.02(s, 2H),5.23(s, 2H), 6.96(d, J=8Hz, 1H), 6.98(d, J=8Hz, 1H), 7.16(s, 1H),7.82(s, 2H), 10.20-11.00(br.s, H)

Example 552[[1-[10-(Methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]piperidin-4-yl]carbamoyl]aminoaceticacid

The title compound was obtained by treatingethyl[(1-benzylpiperidin-4-yl)carbamoyl]aminoacetate by the same methodsas those of Examples 64 and 18.

¹H-NMR(CDCl₃) δ ppm: 1.57-1.68(m, 2H), 2.00-2.10(m, 2H), 2.44-2.57(m,2H), 2.93-2.99(m, 2H), 3.45(s, 2H), 3.56(s, 3H), 3.88-3.99(m, 1H),3.91(s, 2H), 5.25-5.35(br.s, 1H), 5.28(s, 2H), 5.33(br.s, 1H), 6.96(s,2H), 7.14(s, 1H), 7.83(s, 2H)

Examples 553 to 574

The following compounds were obtained by the same method as the one ofExample 64 by using N,N-diisopropylethylamine or anhydrous potassiumcarbonate as a base.

Ex. Structural formula NMR 553

¹H-NMR(CDCl₃) δ ppm: 1.56(br.s, 1H), 1.71-1.78(m, 2H), 2.08-2.20(m, 2H),2.42- 2.53(m, 2H), 2.73-2.81(m, 2H), 3.43(br.s, 2H), 3.63(s, 2H),3.70(s, 3H), 6.46(br.s, 1H), 6.59(br.s, 1H), 6.81(dd, J=1.5, 7.8Hz, 1H),6.85(d, J=7.8Hz, 1H), 7.25-7.30(m, 2H), 7.45- 7.49(m, 2H), 7.58(d,J=2.9Hz, 1H), 7.69(d, # J=2.9Hz, 1H) 554

¹H-NMR(CDCl₃) δ ppm: 0.91-1.03(m, 2H), 1.25(t, J=7.1Hz, 3H),1.41-1.51(m, 2H), 1.63-1.79(m, 3H), 1.94-2.02(m, 2H), 2.15(d, J=7.0Hz,2H), 3.12(s, 2H), 3.15(s, 2H), 3.61 (s, 2H), 4.12(q, J=7.1Hz, 2H),6.64(br.s, 1H), 6.67(br.s, 1H), 6.74(dd, J=1.6, 7.9Hz, 1H), 6.82(d,J=7.9Hz, 1H), 7.57(d, J=2.7Hz, # 1H), 7.68(d, J=2.7Hz, 1H) 555

¹H-NMR(CDCl₃) δ ppm: 1.72-1.86(m, 4H), 2.02-2.10(m, 2H), 2.49(m, 1H),2.95-3.02(m, 2H), 3.38(s, 2H), 3.60(s, 2H), 3.69(s, 3H), 3.81(s, 3H),6.49(br.s, 1H), 6.58(d, J=1.5Hz, 1H), 6.74(d, J=1.5Hz, 1H), 6.78(dd, J=1.5, 7.5Hz, 1H), 6.79(dd, J=1.5, 7.9Hz, 1H), 6.85(d, J=7.9Hz, 1H),7.10(d, J=7.5Hz, 1H), # 7.58(d, J=2.9Hz, 1H), 7.70(d, J=2.9Hz, 1H) 556

¹H-NMR(CDCl₃) δ ppm: 1.28(t, J=7.1Hz, 1.5H), 1.54-1.66(m, 2H),1.93-2.00(m, 2H), 2.01-2.10(m, 2H), 2.78-2.87(m, 3H), 3.25 (s, 1H),3.27(s, 1H), 3.32(s, 2H), 3.74(s, 1.5H), 4.19(q, J=7.1Hz, 1H), 6.54(d,J= 1.5Hz, 1H), 6.73(dd, J=1.5, 7.9Hz, 1H), 6.81 (d, J=7.9Hz, 1H),7.18(br.s, 1H), 7.59(d, J= # 2.9Hz, 1H), 7.69(d, J=2.9Hz, 1H) 557

¹H-NMR(CDCl₃) δ ppm: 1.26(t, J=7Hz, 3H), 1.38(dq, J=3, 12Hz, 2H),1.76(dq, J=3, 12Hz, 2H), 1.99(br.d, J=12Hz, 4H), 2.41(m, 5H), 2.83(m,4H), 3.22(m, 1H), 3.38(s, 2H), 4.14 (q, J=7Hz, 2H), 6.55(d, J=1Hz, 1H),6.74(dd, J=1, 8Hz, 1H), 6.82(d, J=8Hz, 1H), 7.40(br.s, 1H), 7.48(d,J=3Hz, 1H), 7.67(d, J=3Hz, 1H), # 8.20(s, 1H) 558

¹H-NMR(CDCl₃) δ ppm: 2.41(m, 4H), 2.60- 2.69(m, 4H), 3.35(s, 2H),3.48(t, J=5Hz, 2H), 3.61(t, J=5Hz, 2H), 3.69(s, 3H), 6.41(s, 1H),6.53(d, J=2Hz, 1H), 6.77(dd, J=2, 8Hz, 1H), 6.85(d, J=8Hz, 1H), 7.58(d,J=3Hz, 1H), 7.70(d, J=3Hz, 1H) 559

¹H-NMR(CDCl₃) δ ppm: 0.00(s, 9H), 0.99(m, 2H), 1.61(br.s, 2H),1.95(br.d, J=12Hz, 2H), 2.07(br.s, 2H), 2.73(br.s, 2H), 3.29(s, 2H),3.33(m, 1H), 3.93(s, 2H), 4.22(m, 2H), 6.46 (br.s, 1H), 6.58(br.s, 1H),6.69(dd, J=2, 8Hz, 1H), 6.78(d, J=8Hz, 1H), 7.52(d, J=3Hz, 1H), 7.64(d,J=3Hz, 1H) 560

¹H-NMR(CDCl₃) δ ppm: 0.84(t, J=7Hz, 3H), 1.44(q, J=7Hz, 2H),1.47-1.61(m, 4H), 2.30(s, 2H), 2.33-2.40(m, 2H), 2.41-2.49(m, 2H),3.35(s, 2H), 3.54(s, 3H), 6.55(d, J=2Hz, 1H), 6.72(br.s, 1H), 6.74(dd,J=2, 8Hz, 1H), 6.81(d, J=8Hz, 1H), 7.57(d, J=3Hz, 1H), 7.68(d, J=3Hz,1H) 561

¹H-NMR(CDCl₃) δ ppm: 1.22(t, J=7Hz, 3H), 1.5-1.7(m, 3H), 1.7-1.8(m, 2H),1.9-2.15(m, 2H), 2.15-2.28(m, 2H), 2.65-2.75(m, 2H), 3.29(d, J=9Hz, 1H),3.33(d, J=9Hz, 1H), 4.10(q, J=7Hz, 2H), 6.51(br.s, 1H), 6.54(d, J=2Hz,1H), 6.74(dd, J=2, 8Hz, 1H), 6.81(d, J=8Hz, 1H), 7.57(d, J=3Hz, 1H), #7.68(d, J=3Hz, 1H) 562

¹H-NMR(CDCl₃) δ ppm: 1.58(t, J=5Hz, 2H), 1.64(t, J=5Hz, 2H), 2.01(s,2H), 2.03(s, 2H), 2.25(br.s, 2H), 2.23(br.s, 2H), 3.05(quint, J= 9Hz,1H), 3.28(s, 2H), 3.67(s, 3H), 6.39(br.s, 1H), 6.53(br.s, 1H), 6.74(dd,J=2, 8Hz, 1H), 6.82(d, J=8Hz, 1H), 7.57(d, J=3Hz, 1H), 7.68(d, J=3Hz,1H) 563

¹H-NMR(CDCl₃) δ ppm: 1.15(s, 6H), 1.23(t, J=7Hz, 3H), 1.1-1.4(m, 3H),1.52(d, J=6Hz, 2H), 1.50-1.60(m, 2H), 1.8-1.95(m, 2H), 2.78(br.d,J=12Hz, 2H), 3.28(s, 2H), 4.08(q, J=7Hz, 2H), 6.53(d, J=1Hz, 1H), 6.68-6.76(m, 2H), 6.81(d, J=8Hz, 1H), 7.57(d, J=3Hz, 1H), 7.68(d, J=3Hz, 1H)564

¹H-NMR(CDCl₃) δ ppm: 1.24(t, J=7Hz, 3H), 1.4-1.6(m, 1H), 2.02-2.14(m,1H), 2.14-2.24 (m, 1H), 2.4(d, J=8Hz, 2H), 2.46-2.64(m, 3H), 2.80(t,J=8Hz, 1H), 3.44(d, J=13Hz, 1H), 3.48(d, J=13Hz, 1H), 4.11(q, J=7Hz,2H), 6.44-6.50(m, 1H), 6.56(br.s, 1H), 6.74- 6.78(m, 1H), 6.82(d, J=8Hz,1H), 7.57 # (d, J=3Hz, 1H), 7.68(d, J=3Hz, 1H) 565

¹H-NMR(CDCl₃) δ ppm: 1.12(d, J=7Hz, 3H), 1.25(t, J=7Hz, 3H), 1.2-1.45(m,2H), 1.48- 1.60(m, 2H), 1.60-1.75(m, 1H), 1.92(t, J= 10Hz, 2H),2.25(quint, J=7Hz, 1H), 2.8-2.93 (m, 2H), 3.31(s, 2H), 4.12(q, J=7Hz,2H), 6.50-6.56(m, 1H), 6.53(d, J=1Hz, 1H), 6.75 (dd, J=1, 8Hz, 1H),6.82(d, J=8Hz, 1H), 7.57 # (d, J=3Hz, 1H), 7, 68(d, J=3Hz, 1H) 566

¹H-NMR(CDCl₃) δ ppm: 1.11(s, 6H), 1.24(t, J=7Hz, 3H), 1.3-1.45(m, 2H),1.45-1.55(m, 2H), 1.50-1.65(m, 1H), 1.85-1.95(m, 2H), 2.85-2.9(m, 2H),3.31(m, 2H), 4.11(q, J=7Hz, 2H), 6.38-6.44(m, 1H), 6.52(br.s, 1H),6.75(dd, J=1, 8Hz, 1H), 6.82(d, J=8Hz, 1H), 7.57(d, J=2Hz, 1H), 7.69(d,J=2Hz, 1H) 567

¹H-NMR(CDCl₃) δ ppm: 1.25(t, J=7Hz, 3H), 1.28-1.45(m, 1H), 1.53-1.65(m,2H), 1.6-1.70 (m, 2H), 1.70-1.90(m, 2H), 1.85-2.0(m, 2H), 2.30(t, J=8Hz,2H), 2.8-2.9(m, 2H), 3.23 (s, 2H), 4.12(q, J=7Hz, 2H), 6.55(br.s, 1H),6.57(br.s, 1H), 6.74(dd, J=1, 8Hz, 1H), 6.82(d, J=8Hz, 1H), 7.57(d,J=3Hz, 1H), # 7.68(d, J=3Hz, 1H) 568

¹H-NMR(CDCl₃) δ ppm: 1.25(t, J=7.2Hz, 3H), 1.33-1.45(m, 2H),1.75-1.83(m, 2H), 1.93-2.03(m, 2H), 2.41-2.50(m, 1H), 2.75- 2.84(m, 2H),3.29(s, 2H), 3.40(s, 2H), 4.16(q, J=7.2Hz, 2H), 6.53(d, J=1.6Hz, 1H),6.70 (dd, J=1.6, 7.7Hz, 1H), 6.77(d, J=7.7Hz, 1H), 7.37(br.s, 1H),7.55(d, J=2.8Hz, 1H), 7.64 # (d, J=2.8Hz, 1H) 569

¹H-NMR(CDCl₃) δ ppm: 0.73(dd, J=4.6, 6.5Hz, 2H), 1.10(dd, J=4.6, 6.5Hz,2H), 1.22 (t, J=7.1Hz, 3H), 1.35-1.48(m, 2H), 1.53- 1.60(m, 2H),1.63-1.73(m, 1H), 1.86-1.96(m, 2H), 2.83-2.90(m, 2H), 3.30(s, 2H),4.09(q, J=7.1Hz, 2H), 6.48-6.53(br.s, 1H), 6.54(d, J=1.4Hz, 1H),6.75(dd, J=1.4, 8.0Hz, 1H), # 6.82(d, J=8.0Hz, 1H), 7.57(d, J=2.7Hz,1H), 7.68(d, J=2.7Hz, 1H) 570

¹H-NMR(CDCl₃) δ ppm: 1.21-1.35(m, 2H), 1.60-1.70(m, 1H), 1.70-1.77(m,2H), 1.88- 1.98(m, 2H), 2.82-2.88(m, 2H), 3.31(s, 2H), 3.37(d, J=6.7Hz,2H), 3.75(s, 3H), 4.08(s, 2H), 6.51-6.56(br.s, 1H), 6.54(d, J=1.7Hz,1H), 6.75(dd, J=1.7, 7.8Hz, 1H), 6.82(d, J= 7.8Hz, 1H), 7.57(d, J=3.2Hz,1H), 7.68(d, J= # 3.2Hz, 1H) 571

¹H-NMR(CDCl₃) δ ppm: 1.30(t, J=7Hz, 3H), 1.7-1.85(m, 4H), 2.0-2.1(m,2H), 2.4-2.5(m, 1H), 2.9-3.0(m, 2H), 3.38(s, 2H), 4.27(q, J=7Hz, 2H),4.60(s, 2H), 6.59(s, 1H), 6.56- 6.66(m, 1H), 6.79(dd, J=1, 8Hz, 1H),6.84(d, J=8Hz, 1H), 6.85(d, J=9Hz, 2H), 7.14(d, J=9Hz, 2H), 7.58(d,J=3Hz, 1H), 7.69(d, # J=3Hz, 1H) 572

¹H-NMR(CDCl₃) δ ppm: 1.38(t, J=7Hz, 3H), 1.7-1.88(m, 4H), 2.07(dt, J=4,12Hz, 2H), 2.5-2.64(m, 1H), 2.99(br.d, J=12Hz, 2H), 3.39 (s, 2H),4.36(q, J=7Hz, 2H), 6.56(s, 1H), 6.58(d, J=1Hz, 1H), 6.79(dd, 1, 8Hz,1H), 6.85 (d, J=8Hz, 1H), 7.29(d, J=8Hz, 2H), 7.58(d, J=3Hz, 1H),7.70(d, J=3Hz, 1H), 7.98(d, # J=8Hz, 2H) 573

¹H-NMR(CDCl₃) δ ppm: 1.12(d, J=7Hz, 3H), 1.24(t, J=7Hz, 3H), 1.65(m,1H), 1.89(dt, J=7, 13Hz, 1H), 2.35(sex, J=7Hz, 1H), 2.52(m, 1H),2.75(dt, J=3, 7Hz, 2H), 3.42(s, 2H), 3.46(m, 2H), 4.10(q, J=7Hz, 2H),6.43(br.s, 1H), 6.46(d, J=2Hz, 1H), 6.71(dd, J=2, 8Hz, 1H), 6.81(d,J=8Hz, 1H), 7.56(d, J=3Hz, 1H), # 7.68(d, J=3Hz, 1H) 574

¹H-NMR(DMSO-d₆) δ ppm: 1.25(t, J=7.2Hz, 3H), 1.47-1.59(m, 2H),1.60-1.68(m, 2H), 1.88-1.97(m, 2H), 2.69-2.78(m, 2H), 3.24(s, 2H),3.48-3.60(m, 1H), 4.19(q, J=7.2Hz, 2H), 6.69(d, J=7.8Hz, 1H), 6.73(s,1H), 6.84 (d, J=7.8Hz, 1H), 7.63(s, 2H), 8.80(d, J= 8.4Hz, 1H), 9.45(s,1H)

Example 575 Methyl4-[1-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-piperidin-4-yl]phenylacetate

To a solution of 1.0 g of methyl4-[1-(benzyloxy-carbonyl)piperidin-4-yl]phenylacetate in ethanol (100ml) was added 1.0 g of 10% palladium-carbon (moisture content: 50%) anda hydrogenation reaction was effected under atmospheric pressure for 12hours. Then the palladium-carbon was filtered off and the solvent wasconcentrated under reduced pressure to thereby give 0.5 g of crudemethyl 4-(piperidin-4-yl)phenylacetate. To a solution of 0.5 g of thiscrude product and 0.5 g of8-(chloroethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine inN,N-dimethylformamide (30 ml) was added 0.87 g of anhydrous potassiumcarbonate and the resulting mixture was stirred under heating to 60° C.for 40 minutes. After adding water, the reaction mixture was extractedwith ethyl acetate, washed with a saturated aqueous solution of sodiumchloride and dried over anhydrous magnesium sulfate. After distillingoff the solvent under reduced pressure, the residue was purified bysilica gel column chromatography (eluted with n-hexane/ethyl acetate) tothereby give 0.6 g of the title compound as a yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.7-1.85(m, 4H), 2.0-2.1(m, 2H), 2.4-2.54(m, 1H),2.94-3.0(m, 2H), 3.37(s, 2H), 3.59(s, 2H), 3.69(s, 3H), 6.38-6.43(m,1H), 6.55-6.58(m, 1H), 6.76-6.80(m, 1H), 6.84(d, J=8 Hz, 1H), 7.18(d,J=8 Hz, 2H), 7.21(d, J=8 Hz, 2H), 7.57(d, J=3 Hz, 1H), 7.69(d, J=3 Hz,1H)

Examples 576 to 582

The following compounds were obtained by the same method as the one ofExample 575.

Ex. Structural formula NMR 576

¹H-NMR(CDCl₃) δ ppm: 1.76-1.88(m, 2H), 1.92- 2.04(m, 2H), 2.20-2.36(m,2H), 2.65-2.76(m, 2H), 3.37(s, 2H), 3.56(s, 2H), 3.69(s, 3H), 4.31(m,1H), 6.52(br.s, 1H), 6.56(br.s, 1H), 6.77(dd, J=1.6, 7.9Hz, 1H),6.82-6.88(m, 3H), 7.15-7.20(m, 2H), 7.58(d, J=2.7Hz, 1H), 7.69(d,J=2.7Hz, 1H) 577

¹H-NMR(CDCl₃) δ ppm: 1.32-1.46(m, 2H), 1.74- 1.86(m, 2H), 1.93-2.04(m,3H), 2.86-2.94(m, 2H), 3.35(s, 2H), 3.56(s, 2H), 3.68(s, 3H), 3.78(d,J=5.9Hz, 2H), 6.56(br.s, 1H), 6.64(br.s, 1H), 6.77 (dd, J=1.5, 8.0Hz,1H), 6.81-6.86(m, 3H), 7.15- 7.20(m, 2H), 7.58(d, J=2.7Hz, 1H), 7.69(d,J= 2.7Hz, 1H) 578

¹H-NMR(CDCl₃) δ ppm: 1.24-1.88(m, 10H), 2.20-2.30(m, 1H), 2.34, 2.43(m,total2H), 2.58- 2.69(m, 2H), 3.46, 3.49(m, total2H), 3.65, 3.67(s,total3H), 6.50(m, 1H), 6.62(m, 1H), 6.67, 6.78(dd, J=1.6, 7.9Hz,total1H), 6.83, 6.40(d, J=7.9Hz, total1H), 7.57(d, J=2.9Hz, 1H), 7.69(d,J=2.9Hz, 1H) 579

¹H-NMR(CDCl₃) δ ppm: 1.5-1.9(m, 4H), 2.0- 2.1(m, 2H), 2.38-2.48(m, 1H),2.9-3.0(m, 2H), 3.38(s, 2H), 3.63(s, 2H), 3.70(s, 3H), 3.80(s, 3H),3.84(s, 3H), 6.42-6.46(m, 1H), 6.58(d, J=1Hz, 1H), 6.68(d, J=2Hz, 1H),6.72(d, J=2Hz, 1H), 6.79 (dd, J=2, 8Hz, 1H), 6.85(d, J=8Hz, 1H), 7.58(d,J=3Hz, 1H), 7.70(d, J=3Hz, 1H) 580

¹H-NMR(DMSO-d₆) δ ppm: 1.5-1.7(m, 4H), 1.9- 2.0(m, 2H), 2.5-2.66(m, 1H),2.86(br.d, J=12Hz, 2H), 3.30(s, 2H), 3.57(s, 3H), 3.72(s, 2H), 6.72(d,J=8Hz, 1H), 6.79(s, 1H), 6.84(d, J=8Hz, 1H), 7.06-7.18(m, 2H),7.18-7.28(m, 2H), 7.56-7.66(m, 2H), 9.44(s, 1H) 581

¹H-NMR(CDCl₃) δ ppm: 1.7-1.86(m, 4H), 2.0- 2.1(m, 2H), 2.44-2.56(m, 1H),2.94-3.0(m, 2H), 3.38(s, 2H), 3.61(s, 2H), 3.69(s, 3H), 6.40-6.48(m,1H), 6.58(d, J=1Hz, 1H), 6.80(dd, J=1, 8Hz, 1H), 6.85(d, J=8Hz, 1H),7.1-7.18(m, 3H), 7.22-7.3(m, 1H), 7.58(d, J=3Hz, 1H), 7.69(d, J=3Hz, 1H)582

¹H-NMR(DMSO-d₆) δ ppm: 1.00-1.09(m, 5H), 1.03(d, J=7.1Hz, 3H), 1.14(t,J=7.3Hz, 3H), 1.29- 1.40(m, 1H), 1.55-1.60(m, 3H), 1.77-1.87(m, 2H),2.28-2.37(m, 1H), 2.66-2.75(m, 2H), 3.23(s, 2H), 4.03(q, J=7.3Hz, 2H),6.74(dd, J=1.6, 7.9Hz, 1H), 6.79(d, J=1.6Hz, 1H), 6.85(d, J=7.9Hz, 1H),7.93 (s, 1H), 8.22(s, 1H), 9.76(s, 1H)

Example 583Ethyl(E)-3-[1-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)piperidin-4-yl]propanoate

To a solution of 1.6 g of ethyl 3-(1-benzylpiperidin-4-yl)propenoate in1,2-dichloroethane (30 ml) was added at 0° C. 0.74 ml of 1-chloroethylchloroformate and the resulting mixture was stirred at the sametemperature for 15 minutes and then heated under reflux for 1 hour.After distilling off the solvent under reduced pressure, 50 ml ofmethanol was added to the residue and the resulting mixture was heatedunder reflux for 1 hour. Then the mixture was made weakly alkaline witha dilute aqueous solution of sodium hydroxide and the solvent wasdistilled off under reduced pressure. To a solution of 1.0 g of ethyl3-(piperidin-4-yl)propenoate thus obtained and 0.64 g of8-(chloroethyl)-1OH-pyrazino[2,3-b][1,4]benzothiazine inN,N-dimethylformamide (30 ml) was added 1.1 g of anhydrous potassiumcarbonate and the resulting mixture was stirred by heating to 60° C. for1 hour. After adding water, the reaction mixture was extracted withethyl acetate, washed with a saturated aqueous solution of sodiumchloride and dried over anhydrous magnesium sulfate. After distillingoff the solvent under reduced pressure, the residue was purified bysilica gel column chromatography (eluted with methanol/dichloromethane)to thereby give 0.6 g of the title compound as yellow crystals.

¹H-NMR(CDCl₃) δ ppm: 1.29(t, J=3 Hz, 3H), 1.4-1.55(m, 2H), 1.65-1.78(m,2H), 1.93-2.05(m, 2H), 2.07-2.2(m, 1H), 2.8-2.90(m, 2H), 3.33(s, 2H),4.18(q, J=7 Hz, 2H), 5.79(dd, J=1, 16 Hz, 1H), 6.48(s, 1H), 6.52(d, J=,2 Hz, 1H), 6.75(dd, J=2, 8 Hz, 1H), 6.83(d, J=8 Hz, 1H), 6.91(dd, J=6,16 Hz, 1H), 7.57(d, J=3 Hz, 1H), 7.69(d, J=3 Hz, 1H)

Examples 584 to 601

The following compounds were obtained by the same method as the one ofExample 583.

Ex. Structural formula NMR 584

¹H-NMR(CDCl₃)δppm: 1.27(t, J=7Hz, 3H), 2.71(t, J=7Hz, 2H), 2.92- 3.0(m,2H), 3.24(d, J=1Hz, 2H), 3.49(s, 2H), 4.15(q, J=7Hz, 2H), 5.75(t, J=2Hz,1H), 6.47(s, 1H), 6.53(d, J=1Hz, 1H), 6.77(dd, J=1, 8Hz, 1H), 6.84(d,J=8Hz, 1H), 7.57(d, J=3Hz, 1H), # 7.69(d, J=3Hz, 1H) 585

¹H-NMR(CDCl₃)δppm: 1.29(t, J=7Hz, 3H, E), 1.30(t, J=7Hz, 3H, Z),1.34-1.48(m, 2H, Z), 1.44-1.56(m, 2H, E), 1.56-1.63(m, 2H, E),1.63-1.72(m, 2H, Z), 1.84(d, J=2Hz, 3H, E), 1.87(d, J=1Hz, 3H, Z),1.94-2.06(m, 2H, Z+E), 2.24-2.36(m, 1H, E), 2.84-2.96(m, 2H, E+Z), #2.84-2.96(m, 1H, Z), 3.48(s, 3H, Z), 3.50(s, 3H, E), 4.18(q, J=7Hz, 2H,E), 4.18(q, J=7Hz, 2H, Z), 5.73(d, J=9Hz, 1H, Z), 6.59(d, J=9Hz, 1H, E),7.2-7.38(m, 5H, E+Z) 586

¹H-NMR(CDCl₃)δppm: 1.13(d, J=7Hz, 3H), 1.24(t, J=7Hz, 3H), 1.1- 1.3(m,3H), 1.55-1.80(m, 4H), 1.89(br.t, J=13Hz, 2H), 2.45-2.55(m, 1H),2.77-2.8(m, 2H), 3.30(s, 2H), 4.05-4.18(m, 2H), 6.53(d, J=1Hz, 1H),6.64- 6.72(m, 1H), 6.74(dd, J=1, 8Hz, 1H), 6.81(d, J=8Hz, 1H), # 7.57(d,J=3Hz, 1H),7.68(d, J=3Hz, 1H) 587

¹H-NMR(CDCl₃)δppm: 1.0(s, 6H), 1.24-1.38(m, 5H), 1.6-1.7(m, 2H),1.94(br.t, J=12Hz, 2H), 2.21(s, 2H), 2.78(br.d, J=12Hz, 2H), 3.30(s,2H), 3.64(s, 3H), 6.45(s, 1H), 6.53(d, J=1Hz, 1H), 6.75(dd, J=1, 8Hz,1H), 6.83(d, J=8Hz, 1H), 7.57(d, J=3Hz, 1H), 7.69(d, J=3Hz, 1H) 588

¹H-NMR(CDCl₃)δppm: 1.00(t, J=7Hz, 3H), 1.4- 1.5(m, 2H), 2.28(t, J=6Hz,2H), 2.59(t, J=6Hz, 2H), 2.66(s, 2H), 3.11(s, 2H), 3.88(q, J=7Hz, 2H),5.38(s, 1H), 6.28(d, J=2Hz, 1H), 6.48(dd, J=2, 8Hz, 1H), 6.55(s, 1H),6.56(d, J=8Hz, 1H), 7.32(d, J=3Hz, 1H), 7.41(d, # J=3Hz, 1H) 589

¹H-NMR(CDCl₃)δppm: 1.23(t, J=7Hz, 3H), 1.67- 1.8(m, 2H), 2.2-2.28(m,2H), 2.49(t, J=5Hz, 2H), 3.43(s, 2H), 3.66(s, 2H), 4.11(q, J=7Hz, 2H),5.68(s, 1H), 6.56(d, J=2Hz, 1H), 6.74(dd, J=2, 8Hz, 1H), 6.81(d, J=8Hz,1H), 6.82-6.94(m, 1H), 7.57(d, J=3Hz, 1H), # 7.66(d, J=3Hz, 1H) 590

¹H-NMR(CDCl₃)δppm: 0.96(s, 6H), 1.15-1.4(m, 3H), 1.6-1.72(m, 2H),1.87(br.t, J=12Hz, 2H), 2.23(s, 2H), 2.92(br.d, J=12Hz, 2H), 3.31(s,2H), 3.65(s, 3H), 6.53(d, J=1Hz, 1H), 6.55(m, 1H), 6.75(dd, J=2, 8Hz,1H), 6.82(d, J=8Hz, 1H), 7.57(d, J=3Hz, 1H), 7.69(d, J=3Hz, 1H) 591

¹H-NMR(CDCl₃)δppm: 1.28(t, J=7Hz, 3H), 1.17- 1.35(m, 2H), 1.47-1.70(m,3H), 1.85-1.95(m, 2H), 2.06(d, J=7Hz, 2H), 2.14(d, J=1Hz, 3H),2.84(br.d, J=12Hz, 2H), 3.32(s, 2H), 4.14(q, J=7Hz, 2H), 5.63(d, J=1Hz,1H), 6.43(s, 1H), 6.53(d, J=1Hz, 1H), 6.75(dd, J=1, 8Hz, 1H), # 6.83(d,J=8Hz, 1H), 7.57(d, J=3Hz, 1H), 7.69(d, J=3Hz, 1H) 592

¹H-NMR(CDCl₃)δppm: 0.85(d, J=7Hz, 6H), 1.25(t, J=7Hz, 3H), 1.7- 1.9(m,1H), 2.0-2.15(m, 2H), 2.16(d, J=6Hz, 2H), 2.25-2.35(m, 2H), 2.50-2.60(m, 2H), 3.3-3.45(m, 2H), 4.12(q, J =7Hz, 2H), 6.4-6.5(m, 1H), 6.5-6.7(m, 1H), 6.73-6.78(m, 1H), 6.83(d, J=8Hz, 1H), # 7.57(d, J=3Hz, 1H),7.69(d, J=3Hz, 1H) 593

¹H-NMR(DMSO-d₆)δppm: 1.21(t, J=7.1Hz, 3H), 2.35- 2.45(m, 4H), 2.41(br.t,J=5.1Hz, 2H), 2.78(br.t, J=5.1Hz, 2H), 3.29(s, 2H), 4.19(q, J=7.1Hz,2H), 6.71(d, J=7.5Hz, 1H), 6.76(s, 1H), 6.84(d, J=7.5Hz, 1H), 7.63(s,2H), 9.44(s, 1H) 594

¹H-NMR(DMSO-d₆)δppm: 1.20(t, J=7.3Hz, 3H), 1.30- 1.48(m, 3H),1.56-1.64(m, 1H), 1.70-1.92(m, 3H), 2.74-2.84(m, 2H), 3.24(s, 2H),4.16(q, J=7.3Hz, 2H), 4.95(dd, J=4.7, 48.8Hz, 1H), 6.67(d, J=7.6Hz, 1H),6.75(s, 1H), 6.82(d, J=7.6Hz, 1H), 7.62(s, 2H), 9.44(s, 1H)

Examples

The following compounds were obtained by the same method as the one ofExample 66 by using trifluoroacetic acid as a substitute forhydrochloric acid.

Ex. Structural formula NMR 595

¹H-NMR(CDCl₃)δppm: 1.25(t, J=7Hz, 3H), 1.44(dd, J=8, 12Hz, 2H), 1.52(t,J=3Hz, 2H), 1.64(t, J=3Hz, 2H), 2.00(dd, J=8, 12Hz, 2H), 2.22(br.s, 2H),2.32(br.s, 2H), 2.39(d, J=8Hz, 2H), 2.59(sept, J=8Hz, 1H), 3.28(s, 2H),4.10(q, J=7Hz, 2H), 6.51(br.s, # 1H), 6.56(d, J=2Hz, 1H), 6.74(dd, J=2,8Hz, 1H), 6.81(d, J=8Hz, 1H), 7.57(d, J=3Hz, 1H), 7.68(d, J=3Hz, 1H) 596

¹H-NMR(CDCl₃)δppm: 1.27(t, J=7Hz, 3H), 1.65(t, J=5Hz, 4H), 2.32(br.s,4H), 2.54(br.s, 2H), 2.84(d, J=2Hz, 2H), 3.31(s, 2H), 4.14(q, J=7Hz,2H), 5.67(quint, J=2Hz, 1H), 6.42(br.s, 1H), 6.54(d, J=2Hz, 1H),6.75(dd, J=2, 8Hz, 1H), 6.82(d, J=8Hz, 1H), # 7.57(d, J=3Hz, 1H),7.68(d, J=3Hz, 1H) 597

¹H-NMR(CDCl₃)δppm: 1.11(d, J=7Hz, 3H), 1.20(t, J=7Hz, 3H), 1.17-1.64(m,8H), 2.25- 2.42(m, 5H), 3.28(s, 2H), 3.38(d, J=11Hz, 1H), 3.44(d,J=11Hz, 1H), 4.07(q, J=7Hz, 2H), 6.45(s, 1H), 6.50(br.s, 1H), 6.68(dd,J=2, 8Hz, 1H), 6.76(d, J=8Hz, 1H), # 7.50(d, J=3Hz, 1H), 7.62(d, J=3Hz,1H) 598

¹H-NMR(CDCl₃)δppm: 1.20(s, 3H), 1.25(t, J=7Hz, 3H), 1.62(m, 4H), 1.67(d,J=13Hz, 2H), 1.85(d, J=13Hz, 2H), 2.31(br.s, 4H), 2.37(s, 2H), 3.30(s,2H), 4.13(q, J=7Hz, 2H), 6.42(br.s, 1H), 6.55(br.s, 1H), 6.74(dd, J=1,8Hz, 1H), 6.82(d, J=8Hz, 1H), 7.57(d, J=3Hz, 1H), # 7.68(d, J=3Hz, 1H)599

¹H-NMR(CDCl₃)δppm: 1.86(m, 2H), 2.01(m, 2H), 2.35(m, 2H), 2.44(dd, J=7,11Hz, 1H), 2.52(m, 2H), 2.64(dd, J=9, 11Hz, 1H), 3.32(s, 2H), 3.79(s,3H), 4.98(dd, J=7, 9Hz, 1H), 6.53(br.s, 1H), 6.58(br.s, 1H), 6.74(dd,J=2, 8Hz, 1H), 6.82(d, J=8Hz, 1H), 7.57(d, J=3Hz, 1H), 7.68(d, # J=3Hz,1H) 600

¹H-NMR(CDCl₃)δppm: 1.27(t, J=7Hz, 3H), 1.61(m, 4H), 1.70(t, J=1Hz, 3H),2.32(br.s, 4H), 2.47(s, 2H), 2.76(s, 2H), 3.31(s, 2H), 4.16(q, J=7Hz,2H), 6.41(br.s, 1H), 6.54(d, J=2Hz, 1H), 6.76(dd, J=2, 8Hz, 1H), 6.83(d,J=8Hz, 1H), 7.57(d, J=3Hz, 1H), 7.69(d, J=3Hz, 1H) 601

¹H-NMR(CDCl₃)δppm: 1.13(d, J=7Hz, 3H), 1.25(t, J=7Hz, 3H), 1.1- 1.45(m,7H), 1.57-1.70(m, 2H), 1.7-1.83(m, 1H), 1.83-1.95(m, 2H), 2.35- 2.46(m,1H), 2.83(br.d, J=12Hz, 2H), 3.31(s, 2H), 4.12(q, J=7Hz, 2H), 6.54(s,1H), 6.6-6.74(m, 1H), 6.75(dd, J=1, 8Hz, 1H), 6.82(d, # J=3Hz, 1H),7.58(d, J=3Hz, 1H), 7.68(d, J=3Hz, 1H), 8.02(s, 1H)

Examples 602 to 610

The following compounds were obtained by the same method as the one ofExample 66.

Ex. Structural formula NMR 602

¹H-NMR(CDCl₃)δppm: 1.20-1.48(m, 2H), 1.60- 2.18(m, 6H), 2.78-2.88(m,2H), 3.00-3.06(m, 1H), 3.28-3.34(m, 2H), 3.67(s, 2H), 3.72(s, 1H), 5.49-5.54(m, 1H), 6.50-6.56(m, 1H), 6.63-6.98(m, 4H), 7.57(d, J=3Hz, 1H),7.66- 7.70(m, 1H) 603

¹H-NMR(CDCl₃)δppm: 1.21-1.28(m, 3H), 1.68- 1.88(m, 6H), 2.11-2.24(m,2H), 2.33-2.68(m, 5H), 3.46(s, 2H), 4.06-4.13(m, 2H), 6.57-6.61(m, 2H),6.72-6.79(m, 1H), 6.79- 6.84(m, 1H), 7.55-7.59(m, 1H), 7.67-7.69(m, 1H)604

¹H-NMR(CDCl₃)δppm: 1.24(t, J=7.2Hz, 3H), 1.37-1.53(m, 3H), 1.69- 1.78(m,2H), 1.93-2.10(m, 2H), 2.12-2.20(m, 1H), 2.29-2.61(m, 9H), 3.39(s, 2H),4.11(q, J=7.2Hz, 2H), 6.56(d, J=1.2Hz, 1H), 6.65(s, 1H), 6.74(dd, J=1.2,8.0Hz, 1H), 6.80(d, J=8.0Hz, 1H), 7.55-7.58(m, 1H), # 7.66-7.69(m, 1H)605

¹H-NMR(CDCl₃)δppm: 1.06-1.20(m, 2H), 1.22- 1.30(m, 3H), 1.50-2.47(m,10H), 2.56-2.72(m, 2H), 2.83-2.92(m, 1H), 3.51- 3.63(m, 2H),4.09-4.18(m, 2H), 6.58(s, 1H), 6.60(br.s, 1H), 6.77(dd, J=1.2, 8.0Hz,1H), 6.82(d, J=8.0Hz, 1H), 7.57(d, J=3.2Hz, 1H), 7.67-7.70(m, 1H) 606

¹H-NMR(CDCl₃)δppm: 1.89(t, J=7.2Hz, 1H), 1.99(t, J=6.8Hz, 1H),2.16-2.36(m, 4H), 2.54- 2.68(m, 4H), 2.88-3.31(m, 1H), 3.48(s, 2H),3.67(s, 3H), 6.45-6.51(m, 1H), 6.59(br.s, 1H), 6.73- 6.80(m, 1H),6.81-6.86(m, 1H), 7.56-7.59(m, 1H), 7.68-7.71(m, 1H) 607

¹H-NMR(CDCl₃)δppm: 0.52-0.58(m, 1H), 0.63(t, J=4.8Hz, 1H), 0.92- 1.00(m,1H), 1.74-1.96(m, 2H), 2.02-2.12(m, 1H), 2.18-2.32(m, 3H), 2.55- 2.73(m,2H), , 3.26(s, 2H), 3.68(s, 3H), 6.52(s, 1H), 6.62(s, 1H), 6.74(dd,J=2.8, 8.0Hz, 1H), 6.81(d, J=8.0Hz, 1H), 7.57(d, J=2.8Hz, # 7.69(d,J=2.8Hz, 1H) 608

¹H-NMR(CDCl₃)δppm: 1.05-1.20(m, 3H), 1.24(t, J=7.2Hz, 3H), 1.26- 2.13(m,10H), 2.30- 2.42(m, 2H), 2.45-2.70(m, 2H), 2.80-2.95(m, 1H),3.70-4.00(m, 1H), 4.10(q, J=7.2Hz, 2H), 6.52- 6.64(m, 2H), 6.72-6.77(m,1H), 6.78-6.84(m, 1H), 7.56-7.60(m, 1H), 7.67- 7.70(m, 1H) 609

¹H-NMR(CDCl₃)δppm: 1.10-1.24(m, 3H), 1.34- 2.13(m, 10H), 2.56- 2.72(m,1H), 2.84-3.12(m, 2H), 3.67(s, 3H), 3.84- 4.01(m, 1H), 6.50-6.64(m, 2H),6.73-6.77(m, 1H), 6.79-6.84(m, 1H), 7.56- 7.60(m, 1H), 7.67-7.70(m, 1H)610

¹H-NMR(CDCl₃)δppm: 1.03-1.18(m, 2H), 1.21- 1.36(m, 1H), 1.25(t, J=7.0Hz,3H), 1.52- 1.82(m, 5H), 1.82-2.07(m, 3H), 2.15-2.24(m, 1H), 2.35(t,J=7.5Hz, 1H), 2.40-2.60(m, 1H), 2.47(t, J=7.5Hz, 1H), 2.80- 2.90(m, 2H),3.20(s, 2H), 4.12(q, J=7.0Hz, 2H), 6.51(br.s, 1H), 6.56(s, # 1H),6.75(d, J=8.4Hz, 1H), 6.82(d, J=8.4Hz, 1H), 7.57(d, J=2.4Hz, 1H),7.68(d, J=2.4Hz, 1H)

Examples 611 and 612

The following compounds were obtained by the same method as the one ofExample 8.

Ex. Structural formula NMR 611

¹H-NMR(CDCl₃)δppm: 1.14(d, J=7Hz, 3H), 1.25(t, J=7Hz, 3H), 1.3- 1.7(m,7H), 1.7-1.8(m, 2H), 2.2-2.4(m, 2H), 2.30-2.4(m, 1H), 3.08- 3.2(m, 2H),3.66-3.76(m, 2H), 3.75(s, 3H), 4.12(q, J=7Hz, 2H), 6.42(s, 1H),6.76-6.86(m, 1H), 6.92- 7.00(m, 1H), 7.57(d, J=3Hz, 1H), 7.65(d, #J=3Hz, 1H) 612

¹H-NMR(CDCl₃)δppm: 1.14(d, J=7Hz, 3H), 1.26(t, J=7Hz, 3H), 1.0- 1.45(m,8H), 1.55-1.70(m, 2H), 1.65-1.80(m, 1H), 1.80-1.95(m, 2H), 2.35- 2.45(m,1H), 2.83(br.d, J=12Hz, 2H), 3.30(s, 2H), 4.13(q, J=7Hz, 2H), 6.58(s,1H), 6.67(s, 1H), 6.71(dd, J=5, 8Hz, 1H), 6.87(d, J=8Hz, 1H), # 6.87(d,J=8Hz, 1H), 7.18(dd, J=2, 8Hz, 1H), 7.84(dd, J=2, 5Hz, 1H)

Example 613 Ethyl3-[1-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)propyl]piperidin-4-yl]-2-methylbutanoate

To a solution of 2.7 g of3-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl]propylmethanesulfonate in methyl ethyl ketone (50 ml) was added 1.6 g ofsodium iodide and the resulting mixture was reacted at 80° C. for 2hours. After adding ice-water, the reaction mixture was extracted withethyl acetate, washed with a saturated aqueous solution of sodiumchloride and dried over anhydrous magnesium sulfate. After distillingoff the solvent under reduced pressure, a 0.5 g portion of the obtainedbrown oily substance was dissolved in 20 ml of N,N-dimethylformamide.After adding 0.5 g of ethyl 4-(piperidin-4-yl)-2-methylbutanoate and0.44 g of anhydrous potassium carbonate, the resulting mixture wasreacted at 90° C. for 3 hours. After adding water, the reaction mixturewas extracted with ethyl acetate, washed with a saturated aqueoussolution of sodium chloride and dried over anhydrous magnesium sulfate.After distilling off the solvent under reduced pressure, the residue waspurified by silica gel column chromatography (eluted withmethanol/dichloromethane) to thereby give 0.1 g of the title compound asa yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.13(d, J=7 Hz, 3H), 1.25(t, J=7 Hz, 3H),1.14-1.3(m, 6H), 1.36-1.46(m, 1H), 1.5-1.7(m, 2H), 1.72-1.84(m, 2H),1.84-1.96(m, 2H), 2.28-2.42(m, 3H), 2.47(t, J=8 Hz, 2H), 2.86-2.96(m,2H), 4.12(q, J=7 Hz, 2H), 6.35(s, 1H), 6.3-6.4(m, 1H), 6.63-6.68(m, 1H),6.79(d, J=8 Hz, 1H), 7.56(d, J=3 Hz, 1H), 7.68(d, J=3 Hz, 1H)

Example 614Ethyl[1-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-propyl]piperidin-4-yl]carboxylate

To a solution of 0.6 g of3-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl]propionaldehydeand 0.31 g of ethyl isonipecotate in acetonitrile (50 ml) was added 0.2g of sodium borohydride cyanide. Further, acetic acid was added so as tomaintain the pH value at 4. Then the resulting mixture was reacted atroom temperature for 12 hours. After adding an aqueous solution ofsodium hydroxide, the reaction mixture was extracted with ethyl acetate,washed with a saturated aqueous solution of sodium chloride and driedover anhydrous magnesium sulfate. After distilling off the solvent underreduced pressure, the crude product thus obtained was dissolved in 30 mlof tetrahydrofuran. After adding 1 ml of 6 N hydrochloric acid, theresulting mixture was reacted for 1 hour. After adding an aqueoussolution of sodium bicarbonate, the reaction mixture was extracted withethyl acetate, washed with a saturated aqueous solution of sodiumchloride and dried over anhydrous magnesium sulfate. After distillingoff the solvent under reduced pressure, the residue was purified bysilica gel column chromatography (eluted with methanol/dichloromethane)to thereby give 0.39 g of the title compound as a brown oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.25(t, J=7 Hz, 3H), 1.7-1.85(m, 4H), 1.88-2.0(m,2H), 2.0-2.15(m, 2H), 2.25-2.4(m, 1H), 2.36(t, J=8 Hz, 2H), 2.49(t, J=8Hz, 2H), 2.85-2.95(m, 2H), 4, 13(q, J=7 Hz, 2H), 6.34(d, J=2 Hz, 1H),6.46-6.54(m, 1H), 6.56(dd, J=1, 8 Hz, 1H), 6.79(d, J=8 Hz, 1H), 7.56(d,J=3 Hz, 1H), 7.68(d, J=3 Hz, 1H)

Example 615 Ethyl4-[1-[2-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)ethyl]piperidin-4-yl]-2-methylbutanoate

Starting with2-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl]ethylmethanesulfonate and ethyl 4-(piperidin-4-yl)-2-methylbutanoate, ethyl4-[1-[2-10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-ethyl]piperidin-4-yl]-2-methylbutanoatewas obtained by the same method as the one of Example 63. Next, thisproduct was treated by the same method as the one of Example 8 tothereby give the title compound.

¹H-NMR(CDCl₃) δ ppm: 1.14(t, J=7.0 Hz, 3H), 1.20-1.48(m, 9H),1.61-1.77(m, 3H), 2.05-2.14(m, 2H), 2.39(m, 1H), 2.57-2.65(m, 2H),2.69-2.76(m, 2H), 3.03-3.10(m, 2H), 4.13(q, J=7.0 Hz, 2H), 6.40(d, J=1.6Hz, 1H), 6.66(dd, J=1.6, 8.1 Hz, 1H), 6.79(d, J=8.1 Hz, 1H), 6.80(br.s,1H), 7.56(d, J=2.9 Hz, 1H), 7.68(d, J=2.9 Hz, 1H)

Examples 616 to 619

The following compounds were obtained by the same method as the one ofExample 9.

Ex. Structural formula NMR 616

¹H-NMR(CDCl₃)δppm: 1.22(t, J=6Hz, 3H), 1.34- 1.62(m, 2H), 1.64-1.76(m,1H), 1.90-2.00(m, 1H), 1.98-2.06(m, 1H), 2.10- 2.24(m, 1H), 2.50-2.60(m,1H), 2.60-2.80(m, 1H), 2.86-2.96(m, 1H), 3.35(d, J=12Hz, 1H), 3.38(d,J=12Hz, 1H), 4.10(q, J=6Hz, 2H), 4.05-4.15(m, 1H), # 6.54(s, H), 6.76(d,J=8Hz, 1H), 6.93(d, J=8Hz, 1H), 7.55(s, 1H), 7.66(s, 1H) 617

¹H-NMR(CDCl₃)δppm: 1.09(t, J=6Hz, 3H), 1.30- 1.40(m, 1H), 1.50-1.64(m,2H), 1.60-1.80(m, 2H), 1.80-1.90(m, 2H), 2.08(t, J=6Hz, 2H),2.70-2.82(m, 2H), 3.25(s, 2H), 4.08(q, J=6Hz, 2H), 5.73(d, J=16Hz, 1H),6.46(s, 1H), 6.50(s, 1H), 6.68(d, J=8Hz, 1H), 7.76(d, J=8Hz, 1H), 6.83 #(dt, J=6, 16Hz, 1H), 7.49(s, 1H), 7.60(s, 1H) 618

¹H-NMR(CDCl₃)δppm: 2.37(m, 2H), 2.59(t, J=6Hz, 2H), 3.24(br.s, 2H),3.54(s, 2H), 3.73(s, 3H), 6.58(d, J=2Hz, 1H), 6.72(br.s, 1H), 6.78(dd,J=2, 8Hz, 1H), 6.84(d, J=8Hz, 1H), 7.20(m, 1H), 7.56(d, J=3Hz, 1H),7.68(d, J=3Hz, 1H) 619

¹H-NMR(CDCl₃)δppm: 1.13(d, J=7Hz, 3H), 1.24(t, J=7Hz, 3H), 1.1- 1.3(m,6H), 1.35-1.45(m, 1H), 1.6-1.7(m, 2H), 1.85-2.00(m, 2H), 2.3- 2.43(m,1H), 2.86(br.d, J=11Hz, 2H), 3.32(s, 2H), 4.12(q, J=7Hz, 2H), 6.57(br.s,1H), 6.65(dd, J=2, 8Hz, 1H), 6.73(d, # J=8Hz, 1H), 6.9-7.06(m, 1H),7.36(d, J=3Hz, 1H), 7.45(d, J=3Hz, 1H)

Example 620Ethyl[1-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)piperidin-4-yl]propiolate

200 ml of a solution of 19.7 g of triphenylphosphine and 12.4 g ofcarbon tetrabromide in dichloromethane was stirred under ice-cooling and20 ml of a solution of 4.0 g of1-(tert-butoxycarbonyl)piperidine-4-carbaldehyde in dichloromethane wasdropped thereinto. After stirring for 1 hour, the reaction mixture wasdiluted with diethyl ether and filtered through celite to thereby removethe insoluble residue. After distilling off the solvent under reducedpressure, the residue was purified by silica gel column chromatography(eluted with ethyl acetate/n-hexane) to thereby give 5.7 g of4-(2,2-dibromovinyl)-1-(tert-butoxycarbonyl)piperidine as a colorlessoily component. Next, 2.72 g of this product was dissolved in 50 ml ofdry tetrahydrofuran in a nitrogen atmosphere and cooled to −78° C. A 1.0M solution of n-buthyllithium (15 ml; 15 mmol) in hexane was droppedthereinto and the resulting mixture was stirred for 1 hour and then atroom temperature for additional 1 hour. After cooling to −78° C. again,ethyl chloroformate was dropped into the reaction mixture. Then thereaction mixture was brought back to room temperature and distributedinto water and ethyl acetate. The organic layer was extracted, washedwith water and dried over magnesium sulfate. After distilling off thesolvent under reduced pressure, the residue was purified by silica gelcolumn chromatography (eluted with ethyl acetate/n-hexane) to therebygive 2.2 g of ethyl(1-(tert-butoxycarbonyl)piperidin-4-yl)propionate asa colorless oily component. A 1.1 g portion of this product wasdissolved in a mixture of anisole (5 ml) with dichloromethane (5 ml). Tothis solution was added trifluoroacetic acid until the materialdisappeared. The reaction mixture was distributed into an aqueoussolution of potassium carbonate and ethyl acetate. The organic layer wasextracted and dried over potassium carbonate. After distilling off thesolvent under reduced pressure, the residue was dissolved in 20 ml ofN,N-dimethylformamide. After adding 350 mg of potassium carbonate and630 mg of 8-chloromethyl-10H-pyrazino[2.3-b][1,4]benzothiazine, theresulting mixture was heated to 80° C. for 1 hour. Then the reactionmixture was brought back to room temperature and distributed into waterand ethyl acetate. The organic layer was extracted, washed with waterand dried over sodium sulfate. After distilling off the solvent underreduced pressure, the residue was purified by silica gel columnchromatography (eluted with dichloromethane/methanol) to thereby give550 mg of yellow crystals ofethyl[1-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)piperidin-4-yl]propiolate.

1H-NMR(DMSO-d6): 1.19(t, J=6.9 Hz, 3H), 1.48-1.60(m, 2H), 1.75-1.84(m,2H), 2.03-2.13(m, 2H), 2.51-2.68(m,.3H), 3.24(s, 2H), 4.12(g, J=6.9 Hz,2H), 6.68(d, J=8.0 Hz, 1H), 6.74(d, J=1.8 Hz, 1H), 6.83(dd, J=1.8, 8.0Hz, 1H), 7.62(s, 2H), 9.44(s, 1H)

Example 621Ethyl[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.1.0]hex-6-yl]carboxylate

To a solution of 1.523 g ofethyl(3-azabicyclo[3.1.0]hex-6-yl)carboxylate in N,N-dimethylformamide(30 ml) were added 2.30 g of sodium hydrogencarbonate and 1.39 g of8-chloromethyl-10H-pyrazino[2,3-b][1,4]benzothiazine and the resultingmixture was heated to 80° C. for 2 hours. After adding water and ethylacetate, the organic layer was washed with water, dried over magnesiumsulfate and concentrated under reduced pressure. Then the residue waspurified by silica gel column chromatography (eluted withdichloromethane/methanol) to thereby give 0.574 g of the title compoundas pale yellow crystals.

¹H-NMR(CDCl₃) δ ppm: 1.27(t, J=7 Hz, 3H), 1.95(m, 2H), 2.07(t, J=3 Hz,1H), 2.38(d, J=10 Hz, 2H), 3.03(d, J=10 Hz, 2H), 3.44(s, 2H), 4.14(q,J=7 Hz, 2H), 6.41(br.s, 1H), 6.45(d, J=1 Hz, 1H), 6.71(dd, J=1, 8 Hz,1H), 6.81(d, J=8 Hz, 1H), 7.57(d, J=3 Hz, 1H), 7.69(d, J=3 Hz., 1H)

Example 622N-(10-methoxymethyl-10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)chloro-acetamide

1.25 g of8-aminomethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine and0.7 ml of triethylamine were dissolved in N,N-dimethylformamide (15 ml).Under ice-cooling, 2 ml of a solution of 0.4 ml of chloroacetyl chloridein dichloromethane was dropped thereinto and the resulting mixture wasstirred for 1 hour. After adding water, the reaction mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withwater and a saturated aqueous solution of sodium chloride and dried overanhydrous sodium sulfate. After concentrating under reduced pressure,the residue was purified by silica gel column chromatography (elutedwith n-hexane/ethyl acetate). The crystals thus obtained were washedwith n-hexane and thus 1.28 g of the title compound was obtained as ayellow powder.

¹H-NMR(CDCl₃) δ ppm: 3.54(s, 3H), 4.11(s, 2H), 4.43(d, J=5.9 Hz, 2H),5.27(s, 2H), 6.89(br.s, 1H), 6.91(dd, J=1.6, 7.9 Hz, 1H), 7.00(d, J=7.9Hz, 1H), 7.08(d, J=1.6 Hz, 1H), 7.84(d, J=2.7 Hz, 1H), 7.85(d, J=2.7 Hz,1H)

Example 623Ethyl[1-[[(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-carbamoyllmethyl]piperidin-4-yl]carboxylate

0.6 g ofN-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)chloroacetamide wasdissolved in 9 ml of N,N-dimethylformamide. After adding 0.26 g ofanhydrous sodium carbonate and 0.3 g of isonipecotic acid, the resultingmixture was stirred at room temperature for 13 hours. After addingwater, the reaction mixture was extracted with ethyl acetate. The ethylacetate layer was washed with water and a saturated aqueous solution ofsodium chloride, dried over anhydrous sodium sulfate and concentratedunder reduced pressure to thereby give a yellow oily substance.

This oily substance was dissolved in 10 ml of ethanol. After adding 5 mlof 6 N hydrochloric acid, the resulting mixture was stirred for 30minutes. After adding an aqueous solution of sodium carbonate, thereaction mixture was extracted with ethyl acetate. The ethyl acetatelayer was washed with water and a saturated aqueous solution of sodiumchloride, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (eluted with dichloromethane/methanol). The crystals thusobtained were washed with ether and thus 0.64 g of the title compoundwas obtained as a yellow powder.

¹H-NMR(CDCl₃) δ ppm: 1.25(t, J=7.1 Hz, 3H), 1.65-1.78(m, 2H),1.87-1.95(m, 2H), 2.18-2.33(m, 3H), 2.78-2.85(m, 2H), 3.04(s, 2H),4.14(q, J=7.1 Hz, 2H), 4.30(d, J=6.2 Hz, 2H), 6.45(d, J=1.6 Hz, 1H),6.61(br.s, 1H), 6.72(dd, J=1.6, 8.1 Hz, 1H), 6.84(d, J=8.1 Hz, 1H),7.51(m, 1H), 7.57(d, J=2.7 Hz, 1H), 7.69(d, J=2.7 Hz, 1H)

Example 624Ethyl[1-[3-[(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetylamino]propyl]piperidin-4-yl]carboxylate

To 10 ml of N,N-dimethylformamide were added 0.6 g of10H-pyrazino[2,3-b][1,4]benzothiazine-8-acetic acid, 0.8 g of ethyl1-(3-aminopropyl)piperidine-4-carboxylate dihydrochloride, 0.38 g of1-hydroxybenzotriazole, 1.07 ml of triethylamine and 0.53 g of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and the resulting mixturewas stirred at room temperature for 22 hours. After adding water, thereaction mixture was extracted with ethyl acetate. The ethyl acetatelayer was washed with water and a saturated aqueous solution of sodium.chloride, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (eluted with dichloromethane/methanol). The crystals thusobtained were washed with ether and thus 0.72 g of the title compoundwas obtained as a pale brown powder.

¹H-NMR(CDCl₃) δ ppm: 1.28(t, J=7.1 Hz, 3H), 1.60-1.77(m, 4H),1.86-2.05(m, 4H), 2.34(m, 1H), 2.40-2.46(m, 2H), 2.87-2.96(m, 2H),3.30-3.46(m, 2H), 3.34(s, 2H), 4.19(q, J=7.1 Hz, 2H), 6.58(d, J=1.6 Hz,1H), 6.76(dd, J=1.6, 7.9 Hz, 1H), 6.82(d, J=7.9 Hz, 1H), 7.13(br.s, 1H),7.37(m, 1H), 7.55(d, J=2.9 Hz, 1H), 7.66(d, J=2.9 Hz, 1H)

Example 625[10-(Methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl] methylketone

Into a solution of 16 g of10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine-8-carboxaldehydein 200 ml of tetrahydrofuran was dropped at −78° C. 60 ml of a 1.4 Msolution of methyllithium in diethyl ether. Next, the resulting mixturewas heated to room temperature over 2 hours. The reaction mixture waspoured into ice-water and extracted with ethyl acetate. The organiclayer was washed with a saturated aqueous solution of sodium chlorideand dried over anhydrous magnesium sulfate. After distilling off thesolvent under reduced pressure, 16 g of a yellow oily substance wasobtained. To a solution of 16 g of this oily substance indichloromethane (300 ml) was added 100 g of manganese dioxide and theresulting mixture was stirred at room temperature for 17 hours. Afterthe completion of the reaction, the manganese dioxide was filtered off.The filtrate was concentrated and the residue thus obtained was purifiedby silica gel column chromatography (eluted with n-hexane/ethyl acetate)to thereby give 9. 4 g of the title compound. as yellow. crystals.

¹H-NMR(CDCl₃) δ ppm: 2.55(s, 3H), 3.55(s, 3H), 5.31(s, 2H), 7.18(d, J=8Hz, 1H), 7.53(d, J=8 Hz, 1H), 7.69(s, 1H), 7.85(s, 2H)

Example 626[10-(Methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl]bromomethylketone

To a solution of 1.5 g of[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl]methylketone in a mixture of methanol (50 ml) with dichloromethane (100 ml)was added 3.0 g of tetra-n-butylammonium tribromide and the resultingmixture was stirred at room temperature for 4 hours. After distillingoff the solvent, the residue was purified by silica gel columnchromatography (eluted with n-hexane/ethyl acetate) to thereby give 0.9g of the title compound as a yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 3.56(s, 3H), 4.38(s, 2H), 5.30(s, 2H), 7.10(d, J=8Hz, 1H), 7.54(dd, J=2, 8 Hz, 1H), 7.72(d, J=2 Hz, 1H), 7.87(s, 2H)

Example 627 Ethyl4-[1-[2-oxo-2-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl]ethyl]piperidin-4-yl]-2-methylbutanoate

To a solution of 2.6 g of[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl]bromomethylketone and 3.0 g of ethyl 4-(piperidin-4-yl)-2-methylbutanoate inN,N-dimethylformamide (50 ml) was added 2.9 g of anhydrous potassiumcarbonate and the resulting mixture was reacted at room temperature for1.5 hours. After the completion of the reaction, ethyl acetate was addedthereto. The reaction mixture was washed with water and a saturatedaqueous solution of sodium chloride and dried over anhydrous magnesiumsulfate. After concentrating the solvent, the residue was purified bysilica gel column chromatography (eluted with n-hexane/ethyl acetate) tothereby give 2.7 g of ethyl4-1-[2-oxo-2-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl]ethyl]piperidin-4-yl]-2-methylbutanoateas a brown oily substance.

To a solution of 1.7 g of this oily substance in tetrahydrofuran (50 ml)was added 4 ml of 6 N hydrochloric acid and the resulting mixture wasreacted for 1 hour. After adding ethyl acetate, the reaction mixture waswashed with water and a saturated aqueous solution of sodium chlorideand dried over anhydrous magnesium sulfate. After distilling off thesolvent under reduced pressure, the residue was purified by silica gelcolumn chromatography (eluted with n-hexane/ethyl acetate) to therebygive 1.0 g of the title compound as a brown oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.14(d, J=7 Hz, 3H), 1.24(t, J=7 Hz, 3H),1.0-1.4(m, 4H), 1.3-1.5(m, 1H), 1.5-1.8(m, 4H), 2.0-2.1(m, 2H),2.3-2.43(m, 1H), 2.91(br.d, J=10 Hz, 2H), 3.63(s, 2H), 4.11(q, J=7 Hz,2H), 6.52-6.60(m, 1H), 6.93(d, J=8 Hz, 1H), 7.15(d, J=2 Hz, 1H),7.46(dd, J=2, 8 Hz, 1H), 7.60(d, J=3 Hz, 1H), 7.70(d, J=3 Hz, 1H)

Example 628 Ethyl4-[1-[2-hydroxy-2-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl]ethyl]piperidin-4-yl]-2-methylbutanoate

To a solution of 0.8 g of ethyl4-[1-[2-oxo-2-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl]ethyl]piperidin-4-yl]-2-methylbutanoatein ethanol (30 ml) was added 70 mg of sodium borohydride and theresulting mixture was reacted at room temperature for 30 minutes. Afteradding ethyl acetate, the reaction mixture was washed with water and asaturated aqueous solution of sodium chloride and dried over anhydrousmagnesium sulfate. After distilling off the solvent under reducedpressure, the residue was purified by silica gel column chromatography(eluted with n-hexane/ethyl acetate) to thereby give 0.53 g of the titlecompound as a yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.14(d, J=7 Hz, 3H), 1.25(t, J=7 Hz, 3H),1.0-1.5(m, 6H), 1.5-1.8(m, 3H), 2.05-2.2(m, 1H), 2.3-2.6(m, 3H),2.4-2.6(m, 2H), 2.9-3.0(m, 1H), 3.15-3.25(m, 1H), 4.13(q, J=7 Hz, 2H),4.65-4.75(m, 1H), 6.63(s, 1H), 6.4-6.8(m, 1H), 6.7-6.8(m, 1H), 6.83(dd,J=2, 8 Hz, 1H), 7.55(d, J=3 Hz, 1H), 7.66-7.7(m, 1H)

Example 629Ethyl[2-butyl-7-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-7-azaspiro[3.5]non-2-yl]acetate

Ethyl[7-(tert-butoxycarbonyl)-7-azaspiro [3.5]non-2-ylidene]acetate wastreated successively by the same methods as those of Examples 66 and 9to thereby give the title compound.

¹H-NMR(CDCl₃) δ ppm: 0.75(t, J=7 Hz, 3H), 1.07(m, 2H), 1.10(t, J=7 Hz,3H), 1.35(m, 2H), 1.47(m, 6H), 1.54(d, J=13 Hz, 2H)1.65(d, J=13 Hz, 2H),2.16(br.s, 4H), 2.25(s, 2H), 3.15(s, 2H), 3.95(q, J=7 Hz, 2H),6.33(br.s, 1H), 6.41(br.s, 1H), 6.59(dd, J=1, 8 Hz, 1H), 6.65(d, J=8 Hz,1H), 7.42(d, J=3 Hz, 1H), 7.53(d, J=3 Hz, 1H)

Example 630Ethyl[1-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)piperidin-4-yl]butan-1-yl]iminoxyacetate

2.47 g ofethyl[(1-(tert-butoxycarbonyl)piperidin-4-yl]butan-1-yl]iminoxyacetatewas dissolved in 20 ml of dichloromethane and ice-cooled. After adding1.1 ml of iodotrimethylsilane, the resulting mixture was stirred andthen heated to room temperature over 16 hours and 30 minutes. Afteradding 1.0 ml of iodotrimethylsilane, stirring was continued foradditional 1 hour. The reaction mixture was concentrated under reducedpressure and thus a pale brown oily substance was obtained.

The obtained product was dissolved in 20 ml of N,N-dimethylformamide.After adding 1.7 g of8-chloromethyl-10H-pyrazino[2,3-b][1,4]benzothiazine and 9.7 g ofanhydrous potassium carbonate, the resulting mixture was stirred at 80°C. for 2 hours. After adding ethyl acetate, the reaction mixture waswashed with water and a saturated aqueous solution of sodium chlorideand dried over anhydrous magnesium sulfate. After concentrating thesolvent, the residue was purified by silica gel column chromatography(eluted with dichloromethane/methanol) to thereby give 2.8 g of thetitle compound as a yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 0.95(t, J=7.6 Hz, 3H), 1.27(t, J=7.2 Hz, 3H),1.50-1.75(m, 8H), 2.06-2.20(m, 1H), 2.22-2.32(m, 2H), 2.86-2.93(m, 2H),3.23(s, 2H), 4.20(q, J=7.2 Hz, 2H), 4.55(s, 2H), 6.48(br.s, 1H),6.55(br.d, J=1.6 Hz, 1H), 6.76(dd, J=1.6, 7.6 Hz, 1H), 6.83(d, J=7.6 Hz,1H), 7.58(d, J=2.4 Hz, 1H), 7.69(d, J=2.4 Hz, 1H)

Examples 631 to 734

The following compounds were obtained by the same method as the one ofExample 18.

Ex. Structural formula MS M.p. NMR 631

FAB(+) 400(MH⁺) 226- 230° C. (decom- pose) ¹H-NMR (DMSO-d₆) δ ppm:1.58-1.72(m, 2H), 1.74-1.83(m, 2H), 2.07-2.23(m, 3H), 2.27-2.80(m, 2H),2.94(s, 2H), 4.11(d, J=6.0Hz, 2H), 6.66(d, J=1.3Hz, 1H), 6.68(dd, J=1.3,7.9Hz, 1H), 6.85(d, J= #7.9Hz, 1H), 7.63(d, J=2.7Hz, 1H), 7.65(d,J=2.7Hz, 1H), 8.25 (t, J=6.0Hz, 1H), 9.55(s, 1H) 632

FAB(+) 411(MH⁺) 215- 220° C. ¹H-NMR (DMSO-d₆) δ ppm: 0.90-1.34(m, 3H),1.48-1.90(m, 8H), 2.02-2.14(m, 1H), 2.22- 2.60(m, 3H), 2.70-2.82(m, 2H),3.26(s, 2H), 6.67(d, J=8Hz, 1H), 6.74(s, 1H), 6.81(d, J=8Hz, 1H),7.61(d, J=2.8Hz, 1H), 7.62(d, J= # 2.8Hz, 1H), 9.34(s, 1H) 633

FAB(+) 442(MH⁺) 193- 195° C. ¹H-NMR (DMSO-d₆) δ ppm: 0.86(t, J=6.4Hz,3H), 1.38- 1.52(m, 4H), 1.60-1.70(m, 2H), 1.82-1.92(m, 2H), 1.95-2.10(m,1H), 2.10-2.20(m, 2H), 2.75- 2.82(m, 2H), 3.24(s, 2H), 4.00 (s, 2H),6.68(d, J=8.0Hz, 1H), 6.78(s, 1H), 6.81(d, J=8.0Hz, # 1H), 7.61(d,J=2.8Hz, 1H), 7.62 (d, J=2.8Hz, 1H), 9.47(s, 1H) 634

FAB(+) 383(MH⁺) 207- 209° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.50-2.04(m, 7H),2.05(s, 3H), 2.75-2.90(m, 2H), 3.18(s, 2H), 5.57(s, 1H), 6.70(d,J=8.0Hz, 1H), 6.75(s, 1H), 6.83(d, J=8.0Hz, 1H), 7.61(d, J=2.8Hz, 1h),7.63(d, J=2.8Hz, 1H), 9.45(s, 1H) 635

FAB(+) 428(MH⁺) 143° C. (decom- pose) ¹H-NMR (DMSO-d₆) δ ppm:1.45-1.58(m, 4H), 1.72- 1.80(m, 2H), 1.86-1.95(m, 2H), 2.16(m, 1H),2.20- 2.27(m, 2H), 2.72-2.80(m, 2H), 3.00-3.07(m, 2H), 3.21(s, 2H),6.65-6.70(m, 2H), 6.83(d, J=8.2Hz, 1H), 7.64(d, J=2.7Hz, # 1H), 7.65(d,J=2.7Hz, 1H), 8.00(t, J=5.0Hz, 1H), 9.52(s, 1H) 636

FAB(+) 400(MH⁺) 167- 170° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.04-1.15(m, 1H),1.18-1.30(m, 1H), 1.70-1.81(m, 2H), 2.50- 2.62(m, 1H), 2.68(t, J=11.2Hz,2H), 2.97(t, J=11.2Hz, 1H), 3.23(s, 2H), 3.55(s, 2H), 3.70(d, J=12Hz,1H), 4.10(d, J=12Hz, 1H), 6.75(d, J=8.0Hz, 1H), # 6.80(s, 1H), 6.81(d,J=8.0Hz, 1H), 7.60-7.66(m, 2H), 9.45(s, 1H) 637

FAB(+) 371(MH⁺) 200- 204° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.38-1.50(m, 3H),1.65- 1.78(m, 2H), 1.92-2.06(m, 2H), 2.70-2.80(m, 2H), 3.17(s, 2H),6.69(d, J=8.0Hz, 1H), 6.76(s, 1H), 6.82(d, J=8.0Hz, 1H), 7.61(d,J=2.8Hz, 1H), 7.63(d, J=2.8Hz, 1H), 9.46(s, 1H) 638

FAB(+) 400(MH⁺) 121- 124° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.20-1.35(m, 2H),1.56- 1.66(m, 2H), 1.72-1.82(m, 2H), 2.02-2.10(m, 2H), 2.23(t, J=6.8Hz,2H), 2.37(t, J=6.8Hz, 2H), 2.42- 2.50(m, 1H), 2.82-2.90(m, 2H), 3.15(s,2H), 6.74(d, J=8.0Hz, 1H), 6.76(s, 1H), #6.81(d, J=8.0Hz, 1H), 7.61(d,J=2.8Hz, 1H), 7.63(d, J=2.8Hz, 1H), 9.45(s, 1H) 639

FAB(+) 386(MH⁺) 130- 134° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.20-1.34(m, 2H),1.76- 1.87(m, 2H), 2.04-2.14(m, 2H), 2.32(t, J=6.8Hz, 2H), 2.40-2.50(m,1H), 2.59(t, J=6.8Hz, 2H), 2.83-2.92(m, 2H), 3.15(s, 2H), 6.76(d,J=8.0Hz, 1H), 6.77(s, 1H), 6.83(d, J=8.0Hz, 1H), 7.61(d, #J=2.8Hz, 1H),7.63(d, J=2.8Hz, 1H), 9.48(s, 1H) 640

ESI(+) 371(MH⁺) 240- 243° C. ¹H-NMR (DMSO-d₆) δ ppm: 0.99(d, J=6Hz, 3H),1.1- 1.3(m, 2H), 1.3-1.6(m, 3H), 1.81(br.t, J=10Hz, 2H), 2.1-2.2(m, 1H),2.7-2.8(m, 2H), 3.23(s, 2H), 6.65- 6.70(m, 1H), 6.74(s, 1H), 6.81(d,J=8Hz, 1H), 7.62(d, J=3Hz, 1H), 7.63(d, J= #3Hz, 1H), 9.43(s, 1H) 641

ESI(+) 408(MH⁺) 114- 116° C. ¹H-NMR (DMSO-d₆) δ ppm: 2.34-2.60(m, 12H),3.33(s, 2H), 6.71(dd, J=2, 8Hz, 1H), 6.76(d, J=2Hz, 1H), 6.84(d, J=8Hz,1H), 7.62(d, J=3Hz, 1H), 7.63(d, J=3Hz, 1H), 9.45(s, 1H) 650

ESI(+) 355(MH⁺) 200- 203° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.50-1.60(m, 2H),2.42(br.t, J=5Hz, 2H), 2.72(br.t, J=6Hz, 2H), 2.89(s, 2H), 3.30(s, 2H),5.56(s, 1H), 6.68(d, J=8Hz, 1H), 6.74(s, 1H), 6, 83(d, J=8Hz, 1H),7.61(d, J=2Hz, 1H), 7.62(d, J=2Hz, 1H), 9.44(s, 1H), 12.2 # (br.s, 1H)651

ESI(+) 355(MH⁺) 216- 220° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.56-1.66(m, 2H),2.19(t, J=6Hz, 2H), 2.36-2.44(m, 2H), 3.32(s, 2H), 3.51(s, 2H), 5.60(s,1H), 6.68(dd, J=2, 8Hz, 1H), 6.74(d, J=2Hz, 1H), 6.82(d, J=8Hz, 1H),7.61(d, J=3Hz, 1H), 7.62(d, J=3Hz, 1H), 9.42(s, 1H) 652

ESI(+) 357(MH⁺) amor- phous ¹H-NMR (DMSO-d₆) δ ppm: 0.84-0.98(m, 1H),1.36-1.48(m, 1H), 1.50-1.60(m, 1H), 1.60- 1.70(m, 2H), 1.80-1.92(m, 2H),2.06-2.12(m, 2H), 2.56-2.70(m, 2H), 3.23(s, 2H), 6.68(dd, J=1, 8Hz, 1H),6.74(d, J=1Hz, 1H), 6.82(d, J=8Hz, 1H), 7.62(d, J= # 3Hz, 1H), 7.63(d,J=3Hz, 1H), 9.45(s, 1H) 653

ESI(+) 398(MH⁺) 113- 115° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.01(d, J=7Hz, 3H),0.94- 1.22(m, 5H), 1.20-1.40(m, 1H), 1.46-1.62(m, 3H), 1.78-1.88(m, 2H),2.24(q, J=7Hz, 1H), 2.72(br.d, J=12Hz, 2H), 3.23(s, 2H), 6.6-6.74(m,2H), 6.72(s, 1H), 6.82(d, J=8Hz, 1H), 7.2- #7.28(m, 1H), 7.78(dd, J=1,4Hz, 1H), 9.12(s, 1H) 654

ESI(+) 383(MH⁺) 238- 240° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.01(d, J=7Hz, 3H),0.96-1.24 (m, 5H), 1.24-1.38(m, 1H), 1.44-1.60(m, 1H), 1.57(br.d,J=11Hz, 2H), 1.82(t, J=12Hz, 2H), 2.16-2.30(m, 1H), 2.72(br.d, J=11Hz,2H), 3.20(s, 2H), 6.56(dd, J=2, 8Hz, 1H), # 6.58(d, J=2Hz, 1H), 6.67(J=8Hz, 1H), 7.23(d, J=3Hz, 1H), 7.44(d, J=3Hz, 1H), 9.55(br.s, 1H) 655

FAB(+) 399(MH⁺) 219- 220° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.01(d, J=7.1Hz,3H), 1.01- 1.19(m, 5H), 1.25-1.36(m, 1H), 1.45-1.60(m, 3H), 1.77-1.86(m,2H), 2.18- 2.28(m, 1H), 2.67-2.75(m, 2H), 3.14(s, 2H), 6.73(dd, J=1.5,7.9Hz, 1H), 6.79(d, J=7.9Hz, 1H), 6.85(d, J= #1.5Hz, 1H), 7.95(s, 1H),8.22(s, 1H), 9.76(s, 1H) 656

FAB(+) 429(MH⁺) 239- 242° C. ¹H-NMR (DMSO-d₆) δ ppm: 0.9-1.3(m, 5H),1.01(d, J=7Hz, 3H), 1.2-1.4(m, 1H), 1.4-1.75(m, 3H), 1.8-2.1(m, 2H),2.1-2.4(m, 3H), 2.8- 2.95(m, 2H), 4.2-4.35(m, 1H), 6.72(d, J=8Hz, 1H),6.78(d, J=2Hz, 1H), 6.81(d, J=8Hz, 1H), 7.60(d, J= #3Hz, 1H), 7.62(d,J=3Hz, 1H), 9.44(s, 1H) 657

ESI(+) 427(MH⁺) 235- 238° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.01(d, J=7Hz, 3H),1.0- 1.2(m, 5H), 1.26-1.36(m, 1H), 1.46-1.60(m, 1H), 1.50-1.68(m, 4H),1.74- 1.90(m, 2H), 2.16-2.30(m, 3H), 2.37(t, J=9Hz, 2H), 2.76-2.86(m,2H), 6.60(s, 1H), 6.61(d, J=8Hz, 1H), # 6.78(d, J=8Hz, 1H), 7.61(d, J=2Hz, 1H), 7.62(d, J=2Hz, 1H), 9.40(s, 1H) 658

ESI(+) 327(MH⁺) 242- 244° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.42-1.58(m, 2H),1.70- 1.80(m, 2H), 1.84-2.0(m, 2H), 2.10-2.25(m, 1H), 2.64-2.76(m, 2H),3.24(s, 2H), 6.57(dd, J=1, 8Hz, 1H), 6.60(s, 1H), 6.68(d, J=8Hz, 1H),7.24(d, J=3Hz, 1H), 7.44(d, J=3Hz, 1H), 9.57 # (s, 1H) 659

ESI(+) 432(MH⁺) 266- 269° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.84-2.08(m, 4H),2.68- 2.80(m, 1H), 2.90-3.08(m, 2H), 3.28-3.42(m, 2H), 3.51(s, 2H),4.06-4.16(m, 2H), 6.82(s, 1H), 7.00(d, J=8Hz, 1H), 7.0-7.1(m, 1H),7.14(d, J=8Hz, 2H), 7.19(d, J=8Hz, 2H), 7.65(d, J=3Hz, # 1H), 7.66(d,J=3Hz, 1H), 9.73(s, 1H) 660

ESI(+) 413(MH⁺) Amor- phous ¹H-NMR (DMSO-d₆) δ ppm: 1.01(d, J=7Hz, 3H),0.98- 1.38(m, 8H), 1.42-1.54(m, 1H), 1.58(br.d, J=12Hz, 2H),1.82-1.94(m, 2H), 2.22-2.34(m, 1H), 2.74(br.d, J=18Hz, 2H), 3.25(s, 2H),6.68(d, J=8Hz, 1H), 6.74(s, 1H), 6.82(d, J=8Hz, 1H), # 7.58- 7.66(m,2H), 9.44(s, 1H) 661

ESI(+) 412(MH⁺) oily substance ¹H-NMR (DMSO-d₆) δ ppm: 0.95-1.36(m, 8H),1.01(d, J=7Hz, 3H), 1.40-1.62(m, 3H), 1.80-1.90(m, 2H), 2.20-2.32(m,1H), 2.70- 2.80(m, 2H), 3.26(s, 2H), 6.66-6.72(m, 2H), 6.79(s, 1H),6.83(d, J=8Hz, 1H), 7.25(d, J=7Hz, 1H), 7.78(d, # J=5Hz, 1H), 9.13(s,1H) 662

ESI(+) 419(MH⁺) 265- 268° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.9-2.1(m, 4H),2.85(br.s, 1H), 3.00(br.s, 2H), 3.39(br.s, 2H), 4.10(br.s, 2H),6.82(br.s, 1H), 6.97- 7.06(m, 1H), 6.97-7.12(m, 1H), 7.33(d, J=8Hz, 2H),7.65(d, J=2Hz, 1H), 7.66(d, J=2Hz, 1H), 7.89(d, J=8Hz, # 2H), 9.73(br.s,1H), 12.9(br.s, 1H) 663

ESI(+) 449(MH⁺) 258- 262° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.50-1.75(m, 4H),1.95- 2.10(m, 2H), 2.35-2.55(m, 2H), 2.87(br.d, J=11Hz, 1H), 3.32(s,2H), 4.53(s, 2H), 6.72(d, J=8Hz, 1H), 6.78(d, J=8Hz, 2H), 6.79(s, 1H),6.84(d, J=8Hz, 1H), 7.11(d, J=8Hz, 2H), 7.62(d, J= # 3Hz, 1H), 7.63(d,J=3Hz, 1H), 9.46(s, 1H) 664

ESI(+) 429(MH⁺) 155- 160° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.02(d, J=7Hz, 3H),1.10- 1.25(m, 5H), 1.45-1.65(m, 4H), 1.88-2.00(m, 2H), 2.20- 2.32(m,1H), 2.78(br.d, J=12Hz, 2H), 3.30(s, 2H), 3.65(s, 3H), 6.57(s, 1H),6.83(s, 1H), 7.57(d, J=3Hz, 1H), 7.60(d, J=3Hz, 1H), 9.28(s, 1H) 665

ESI(+) 433(MH⁺) 130- 132° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.50-1.76(m, 4H),1.96- 2.08(m, 2H), 2.40-2.52(m, 1H), 2.88(br.d, J=11Hz, 2H), 3.32(s,2H), 3.51(s, 2H), 6.72(dd, J=1, 8Hz, 1H), 6.79(s, 1H), 6.84(d, J=8Hz,1H), 7.05(d, J=8Hz, 1H), 7.09(d, J=8Hz, 1H), 7.10(s, # 1H), 7.21(t,J=8Hz, 1H), 7.62(d, J=3Hz, 1H), 7.63(d, J=3Hz, 1H), 9.45(s, 1H) 666

ESI(+) 433(MH⁺) 152- 154° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.56-1.80(m, 4H),1.96-2.20(m, 2H), 2.58-2.72(m, 1H), 2.84- 2.96(m, 2H), 3.38(s, 2H), 3.61(s, 2H), 6.74(d, J=8Hz, 1H), 6.79(s, 1H), 6.86(d, J=8Hz, 1H), 7.10(t,J=7Hz, 1H), 7.15(d, J= 7Hz, 1H), 7.21(t, J=7Hz, 1H), # 7.24(d, J=7Hz,1H), 7.62(d, J= 2Hz, 1H), 7.63(d, J=2Hz, 1H), 9.47(s, 1H) 667

ESI(+) 463(MH⁺) 174- 176° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.53-1.68(m, 4H),1.96- 2.08(m, 2H), 2.80-2.92(m, 3H), 3.33(s, 2H), 3.45(s, 2H), 3.74(s,3H), 6.72(dd, J=1, 8Hz, 1H), 6.80(d, J=1Hz, 1H), 6.84(d, J=8Hz, 1H),6.86(d, J=8Hz, 1H), 7.00-7.08(m, 1H), 7.04(s, 1H), # 7.62(d, J=3Hz, 1H),7.63(d, J=3Hz, 1H), 9.45(s, 1H) 668

ESI(+) 493(MH⁺) 138- 140° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.55-1.75(m, 4H),1.93- 2.05(m, 2H), 2.35-2.48(m, 1H), 2.83-2.93(m, 2H), 3.29(s, 2H),3.46(s, 2H), 3.63(s, 3H), 3.77(s, 3H), 6.64(d, J=2Hz, 1H), 6.72 (dd,J=2, 8Hz, 1H), 6.78(s, 1H), 6.79(s, 1H), 6.84(d, J=8Hz, # 1H), 7.62(d,J=3Hz, 1H), 7.63(d, J=3Hz, 1H), 9.44(s, 1H) 669

ESI(+) 399(MH⁺) 272- 275° C. ¹H-NMR (CD₃OD) δ ppm: 1.02(s, 6H),1.50-1.75(m, 3H), 1.95-2.05(m, 2H), 2.24(s, 2H), 2.85-2.98(m, 2H),3.45-3.55(m, 2H), 4.09(s, 2H), 6.77(d, J=2Hz, 1H), 6.91(dd, J=2, 8Hz,1H), 6.96(d, J=8Hz, 1H), 7.61(d, J=3Hz, 1H), 7.61(d, J=3Hz, 1H) 670

ESI(+) 413(MH⁺) 230- 232° C. ¹H-NMR (CD₃OD) δ ppm: 1.04(s, 6H), 1.38(d,J=5Hz, 2H), 1.45-1.60(m, 2H), 1.65- 1.70(m, 1H), 1.92-2.03(m, 2H),2.20(s, 2H), 2.78- 3.00(m, 2H), 3.36(br.d, J=8Hz, 2H), 4.05(s, 2H),6.76(d, J=2Hz, 1H), 6.90(dd, J=2, 8Hz, 1H), 6.95(d, J= #8Hz, 1H),7.60(d, J=3Hz, 1H), 7.61(d, J=3Hz, 1H) 671

FAB(+) 505(MH⁺) 54- 55° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.41-1.56(m, 4H),1.75- 1.89(m, 4H), 2.05-2.16(m, 2H), 2.31-2.38(m, 1H), 2.65- 2.72(m,2H), 2.74-2.82(m, 2H), 2.96-3.04(m, 1H), 3.30(s, 2H), 3.31-3.42(m, 2H),6.71(s, 1H), 6.72(d, J=8Hz, 1H), 6.86(d, J=8Hz, # 1H), 7.26(s, 1H),7.64(s, 2H), 9.45(s, 1H) 672

FAB(+) 451(MH⁺) 195- 196° C. ¹H-NMR (CD₃OD) δ ppm: 1.50-1.61(m, 2H),1.82- 1.98(m, 2H), 2.07-2.15(m, 2H), 2.79-2.85(m, 2H), 3.14- 3.21(m,1H), 3.35(s, 2H), 3.50(s, 2H), 6.66(d, J=2Hz, 1H), 6.76(dd, J=2, 8Hz,1H), 6.80(d, J=8Hz, 1H), 7.55(d, J=3Hz, 1H), 7.57(d, J= #3Hz, 1H) 673

FAB(+) 399(M⁺) 240- 242° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.95(dd, J=6, 7Hz,2H), 2.22-2.26(br.s, 2H), 2.27- 2.32(br.s, 2H), 2.35(dd, J=7, 9Hz, 2H),3.28(s, 2H), 3.34-3.42(m, 4H), 6.70(dd, J=1, 8Hz, 1H), 6.77(d, J=1Hz,1H), 6.83(d, J=8Hz, 1H), 7.62(d, J=3Hz, # 1H), 7.63(d, J=3Hz, 1H),9.52(s, 1H) 674

FAB(+) 315(MH⁺) 181- 183° C. ¹H-NMR (CD₃OD) δ ppm: 3.65-3, 72(m, 1H),4.25- 4.35(m, 6H), 6.71(s, 1H), 6.86(d, J=8Hz, 1H), 6.96(d, J=8Hz, 1H),7.62(s, 2H) 675

FAB(+) 357(MH⁺) Amor- phous ¹H-NMR (DMSO-d₆) δ ppm: 0.80(d, J=7Hz, 3H),1.24- 1.31(m, 1H), 1.65-1.74(m, 2H), 2.38-2.45(m, 1H), 2.59(t, J=7Hz,2H), 3.20- 3.27(m, 2H), 3.28(s, 2H), 6.64(dd, J=2, 7Hz, 1H), 6.71(d,J=2Hz, 1H), 6.78(d, J= 7Hz, 1H), 7.61(d, J=3Hz, 1H), # 7.62(d, J=3Hz,1H), 9.53(s, 1H) 676

FAB(+) 385(MH⁺) 225- 226° C. ¹H-NMR (DMSO-d₆) δ ppm: 0.80(t, J=7Hz, 3H),1.43(br.s, 2H), 1.70(br.s, 4H), 2.25(br.s, 2H), 2.80(br.s, 4H), 3.80(s,2H), 6.84(s, 1H), 6.89(d, J=8Hz, 1H), 6.96(br.s, 1H), 7.63(s, 2H),9.42(br.s, 1H) 677

FAB(+) 397(MH⁺) 207- 209° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.36(dd, J=10,11Hz, 2H), 1.42(t, J=5Hz, 2H), 1.52(m, 2H), 1.87(t, J=10Hz, 2H),2.14(br.s, 2H), 2.22(br.s, 2H), 2.28(d, J=8Hz, 2H), 2.46(m, 1H), 3.18(s,2H), 6.67(dd, J=2, 8Hz, 1H), 6.74(d, J=2Hz, 1H), 6.81(d, J= # 8Hz, 1H),7.61(d, J=3Hz, 1H), 7.62(d, J=3Hz, 1H), 9.41(s, 1H) 678

FAB(+) 398(MH⁺) 210- 215° C. ¹H-NMR (DMSO-d₆) δ ppm: 0.95(d, J=8Hz, 3H),1.02- 1.21(m, 5H), 1.44-1.58(m, 4H), 1.79(m, 2H), 2.09(m, 1H), 2.70(d,J=10Hz, 2H), 3.21(s, 2H), 6.51(d, J=5Hz, 1H), 6.65(s, 1H), 6.66(d,J=8Hz, 1H), 6.81(d, J=8Hz, 1H), 7.84(s, 1H), 7.94(d, J= #5Hz, 1H),9.10(s, 1H) 679

FAB(+) 395(MH⁺) 238- 241° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.54(m, 4H),2.22(br.s, 4H), 2.49(br.s, 2H), 2.71(br.s, 2H), 3.24(s, 2H), 5.57(br.s,1H), 6.68(d, J=8Hz, 1H), 6.75(s, 1H), 6.82(d, J=8Hz, 1H), 7.62(d, J=3Hz,1H), 7.63(d, J=3Hz, 1H), 9.44(s, 1H), 11.85(br.s, 1H) 680

FAB(+) 441(MH⁺) 226- 227° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.02(t, J=7Hz, 3H),1.47(m, 2H), 1.54(m, 2H), 1.81(d, J=13Hz, 2H), 1.90(d, J=13Hz, 2H),2.29(br.s, 4H), 2.46(s, 2H), 3.18(s, 2H), 3.30(q, J=7Hz, 2H), 6.67(dd,J=2, 8Hz, 1H), 6.73(d, J=2Hz, 1H), 6.81(d, J=8Hz, 1H), # 7.62(d, J=3Hz,1H), 7.63(d, J=3Hz, 1H), 9.42(s, 1H) 681

FAB(+) 429(MH⁺) 105- 110° C. ¹H-NMR (CD₃OD) δ ppm: 1.04(d, J=7Hz, 3H),1.2- 1.5(m, 8H), 2.21(m, 3H), 2.29(m, 2H), 3.16(s, 2H), 3.42(s, 2H),5.74(s, 1H), 6.67(dd, J=2, 8Hz, 1H), 6.75(d, J=2Hz, 1H), 6.81(d, J=8Hz,1H), 7.62(d, J=3Hz, 1H), 7.63(d, J=3Hz, 1H), 9.43 # (br.s, 1H) 682

FAB(+) 405(MH⁺) 230- 232° C. ¹H-NMR (CD₃OD) δ ppm: 1.61(t, J=11Hz, 2H),1.68(t, 11Hz, 2H), 1.96(s, 2H), 1.98(s, 2H), 2.4-2.8(br.m, 5H), 3.41(s,2H), 6.66(d, J=2Hz, 1H), 6.78(dd, J=2, 8Hz, 1H), 6.83(d, J=8Hz, 1H),7.56(d, J=3Hz, 1H), 7.58(d, J=3Hz, 1H) 683

FAB(+) 409(MH⁺) 251- 252° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.51(m, 4H),1.58(s, 3H), 2.2(br.s, 4H), 2.43(s, 2H), 2.66(s, 2H), 3.22(s, 2H),6.68(d, J=8Hz, 1H), 6.75(d, J=2Hz, 1H), 6.82(dd, J=2, 8Hz, 1H), 7.62(m,2H), 9.42(br.s, 1H) 684

FAB(+) 410(M⁺) 169- 172° C. ¹H-NMR (DMSO-d₆) δ ppm: 0.92(d, J=7Hz, 3H),1.3- 1.42(m, 5H), 1.52(br.s, 2H), 1.74-1.85(m, 2H), 2.10- 2.26(m, 5H),3.22(s, 2H), 6.69(d, J=8Hz, 1H), 6.75(s, 1H), 6.83(d, J=8Hz, 1H),7.63(m, 2H), 9.43(br.s, 1H) 685

FAB(+) 411(MH⁺) 149- 151° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.25(s, 3H),1.72(d, J=13Hz, 2H), 1.78(br.s, 4H), 2.02(d, J=13Hz, 2H), 2.33(s, 2H),2.88(br.s, 4H), 3.84(s, 2H), 6.69(d, J=2Hz, 1H), 6.85(dd, J=2, 8Hz, 1H),6.92(d, J= 8Hz, 1H), 7.60(d, J=3Hz, 1H), # 7.61(d, J=3Hz, 1H), 9.42(s,1H) 686

FAB(+) 383(MH⁺) 265- 268° C. ¹H-NMR (CD₃OD) δ ppm: 1.71(m, 2H), 1.87(s,2H), 2.05-2.15(m, 4H), 2.95- 3.10(m, 5H), 3.97(s, 2H), 6.74(d, J=2Hz,1H), 6.89(dd, J=2, 8Hz, 1H), 6.96(d, J=8Hz, 1H), 7.61(s, 2H) 687

FAB(+) 453(MH⁺) 133- 135° C. ¹H-NMR (CD₃OD) δ ppm: 0.92(t, J=7Hz, 3H),1.21- 1.33(m, 4H), 1.55(m, 2H), 1.67(d, J=13Hz, 2H), 1.75(m, 4H),1.95(d, J=13Hz, 2H), 2.32(s, 2H), 2.50(br.s, 2H), 2.75(br.s, 2H),3.68(s, 2H), 6.67(d, J=2Hz, 1H), 6.82(dd, J=2, 8Hz, 1H), 6.88(d, #J=8Hz, 1H), 7.58(d, J=3Hz, 1H), 7.59(d, J=3Hz, 1H) 688

FAB(+) 369(MH⁺) 229- 230° C. ¹H-NMR (CD₃OD) δ ppm: 2.19(t, J=8Hz, 6H),3.43(t, J=8Hz, 6H), 4.19(s, 2H), 6.71(d, J=2Hz, 1H), 6.88(dd, J=2, 8Hz,1H), 6.99(d, J=8Hz, 1H), 7.62(s, 2H) 689

FAB(+) 341(MH⁺) >275° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.83(s, 2H), 2.31(d,J=10Hz, 2H), 2.91(d, J=10Hz, 2H), 3.29(s, 2H), 3.38(s, 1H), 6.64(d,J=7Hz, 1H), 6.72(s, 1H), 6.81(d, J=7Hz, 1H), 7.62(d, J=3Hz, 1H), 7.63(d,J=3Hz, 1H), 9.44(s, 1H) 690

FAB(+) 385(MH⁺) 178- 180° C. 1H-NMR (CD₃OD) δ: 1.81-1.95(m, 3H), 2.00-2.09(m, 1H), 2.31(dd, J=7, 11Hz, 1H), 2.66(dd, J=9, 11Hz, 1H),2.78(br.s, 2H), 3.31(s, 2H), 3.58(br.s, 2H), 4.74(dd, J=7, 9Hz, 1H),6.68(d, J=2Hz, 1H), 6.81(dd, J=2, 8Hz, 1H), 6.86(d, J=8Hz, 1H), 7.57 #(d, J=3Hz, 1H), 7.59(d, J=3Hz, 1H) 691

ESI(+) 372(MH⁺) 206- 208° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.43-1.53(m, 2H),1.80- 1.92(m, 4H), 2.73-2.86(m, 3H), 3.11(s, 2H), 3.24(s, 2H), 6.67(dd,J=1.9, 7.4Hz, 1H), 6.72(d, J=1.9Hz, 1H), 6.83(d, J=7.4Hz, 1H), 7.62(s,2H), 9.46(s, 1H) 692

ESI(+) 387(MH⁺) 146- 148° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.59-1.72(m, 2H),1.43- 1.57(m, 1H), 1.57-1.66(m, 2H), 1.82-1.92(m, 2H), 2.71- 2.79(m,2H), 3.14(s, 2H), 3.27(d, J=6.3Hz, 2H), 3.94(s, 2H), 6.68(dd, J=2.0,8.7Hz, 1H), 6.75(d, J=2.0Hz, 1H), 6.82(d, J=8.7Hz, 1H), 7.61(d, J=2.7Hz,# 1H), 7.63(d, J=2.7Hz, 1H), 9.43(s, 1H) 693

FAB(+) 400(MH⁺) 149- 151° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.28-1.41(m, 2H),1.65-1.73(m, 2H), 1.93-2.02(m, 2H), 2.65- 2.73(m, 2H), 3.07(s, 2H),3.25(s, 2H), 3.43-3.55(m, 1H), 6.67(dd, J=1.3, 7.4Hz, 1H), 6.74(d, J=1.3Hz, 1H), 6.83(d, J=7.4Hz, 1H), 7.62(d, J=2.9Hz, 1H), # 7.63(d,J=2.9Hz, 1H), 8.00(d, J=8.0Hz, 1H), 9.45(s, 1H) 694

ESI(+) 373(MH⁺) 167- 173° C. ¹H-NMR (DMSO-d₆) δ ppm: 2.34-2.39(m, 2H),2.39- 2.45(m, 4H), 2.75-2.81(m, 2H), 3.32(s, 2H), 6.71(d, J=7.9Hz, 1H),6.76(s, 1H), 6.85(d, J=7.9Hz, 1H), 7.62(s, 2H), 9.46(s, 1H) 695

ESI(+) 375(MH⁺) 163° C. (decom- pose) ¹H-NMR (DMSO-d₆) δ ppm:1.35-1.52(m, 3H), 1.59- 1.67(m, 1H), 1.70-1.88(m, 1H), 1.92-2.07(m, 2H),2.83-2.91(m, 2H), 3.34(s, 2H), 4.77(dd, J=4.5, 49.2Hz, 1H), 6.70(d,J=7.7Hz, 1H), 6.74(s, 1H), 6.83(d, J=7.7Hz, 1H), # 7.61(d, J=2.8Hz, 1H),7.62(d, J=2.8Hz, 1H), 9.46(s, 1H) 696

ESI(+) 367(MH⁺) 155- 156° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.50-1.61(m, 2H),1.76- 1.85(m, 2H), 2.15-2.25(m, 2H), 2.54-2.72(m, 3H), 3.14(s, 2H),6.71(dd, J=1.2, 7.7Hz, 1H), 6.74(d, J=1.2Hz, 1H), 6.84(d, J=7.7Hz, 1H),7.61(d, J=2.5Hz, 1H), 7.63(d, J=2.5Hz, 1H), # 9.47(s, 1H) 697

ESI(+) 399(MH⁺) 221- 222° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.01(d, J=6.5Hz,3H), 1.02- 1.21(m, 5H), 1.24-1.38(m, 1H), 1.44-1.65(m, 3H), 1.79-1.99(m, 2H), 2.20-2.27(m, 1H), 2.69-2.82(m, 2H), 3.15(s, 2H), 6.69(d,J=7.9Hz, 1H), 6.80(br.s, 1H), 6.87(br.d, J=7.9Hz, 1H), # 7.60(d,J=2.6Hz, 1H), 7.62(d, J=2.6Hz, 1H), 9.48(s, 1H) 698

ESI(+) 383(MH⁺) 228- 231° C. ¹H-NMR (DMSO-d₆) δ ppm: 0.63-0.69(m, 2H),0.90- 0.95(m, 2H), 1.31-1.51(m, 5H), 1.71-1.84(m, 2H), 2.71- 2.81(m,2H), 3.20(s, 2H), 6.67(dd, J=1.6, 8.7Hz, 1H), 6.74(d, J=1.6Hz, 1H),6.81(d, J=8.7Hz, 1H), 7.61(d, J=2.5Hz, 1H), 7.62 # (d, J=2.5Hz, 1H),9.43(s, 1H) 699

FAB(+) 386(MH⁺) 222- 226° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.52-1.66(m, 2H),1.66- 1.76(m, 2H), 2.21-2.35(m, 2H), 2.85-2.96(m, 2H), 3.51(s, 2H),3.55-3.65(m, 1H), 6.74(d, J=7.7Hz, 1H), 6.85(s, 1H), 6.87(d, J= 7.7Hz,1H), 7.63(s, 2H), 8.48(d, J=9.0Hz, 1H), 9.52(s, 1H) 700

ESI(+) 397(MH⁺) 126- 130° C. ¹H-NMR (CD₃OD) δ ppm: 1.30-1.45(m, 2H),1.70-1.88(m, 3H), 2.07(d, J=1Hz, 3H), 2.09 (d, J=8Hz, 2H), 2.55-2.65(m,2H), 3.20-3.30(m, 2H), 3.82(s, 2H), 5.66(d, J=1Hz, 1H), 6.70 (d, J=2Hz,1H), 6.85(dd, J=2, 8Hz, 1H), 6.90(d, J=8Hz, 1H), # 7.59(d, J=3Hz, 1H),7.60(d, J=3Hz, 1H) 701

ESI(+) 385(MH⁺) 200° C. (decom- pose) ¹H-NMR (DMSO-d₆) δ ppm: 0.77(d,J=7Hz, 6H), 1.69(m, 2H), 1.82(m, 2H), 2.01(m, 2H), 2.09(m, 1H), 2.34(d,J=10Hz, 2H), 3.20(s, 2H), 6.67(d, J=8Hz, 1H), 6.73(s, 1H), 6.81(d,J=8Hz, 1H), 7.55- 7.70(m, 2H), 9.45(s, 1H) 702

FAB(+) 449(MH⁺) 192° C. (decom- pose) ¹H-NMR (CD₃OD) δ ppm: 1.81-1.89(m,2H), 2.15- 2.28(m, 2H), 3.30-3.40(m, 4H), 3.56(s, 2H), 4.15(s, 2H),6.82(s, 1H), 6.95- 6.98(m, 2H), 7.28-7.32(m, 2H), 7.36-7.40(m, 2H),7.61(d, J=2.9Hz, 1H), 7.62(d, J=2.9Hz, 1H) 703

FAB(+) 397(MH⁺) 145° C. (decom- pose) ¹H-NMR (CD₃OD) δ ppm: 0.93-1.06(m,2H), 1.49-1.58(m, 2H), 1.64-1.77(m, 3H), 1.97- 2.04(m, 2H), 2.08(d,J=6.8Hz, 2H), 3.67(s, 2H), 3.76(m, 2H), 4.07(s, 2H), 6.69(d, J=1.6Hz,1H), 6.85(dd, J=1.6, 7.9Hz, 1H), 6.92(d, J=7.9Hz, 1H), 7.60(d, #J=2.9Hz, 1H), 7.10(d, J=2.9Hz, 1H) 704

FAB(+) 397(MH⁺) 146° C. (decom- pose) ¹H-NMR (CD₃OD) δ ppm: 1.39-1.62(m,4H), 1.68- 1.94(m, 6H), 2.12-2.23(m, 1H), 2.90, 3.04(s, total 2H),3.16-3.24(m, 2H), 3.98, 4.02(s, total 2H), 6.72-6.76(m, 1H), 6.86-6.94(m, 2H), 7.58-7.63(m, 2H) 705

FAB(+) 471(MH⁺) 261- 265° C. (decom- pose) ¹H-NMR (DMSO-d₆) δ ppm:1.52-1.62(m, 2H), 1.83- 1.92(m, 2H), 2.11-2.20(m, 2H), 2.56-2.66(m, 2H),3.13(s, 2H), 3.27(s, 2H), 4.26(m, 1H), 6.69(d, J=7.9Hz, 1H),6.72-6.83(m, 4H), 7.05-7.11(m, 2H), 7.59- 7.63(m, 2H), 9.49(br.s, 1H)706

FAB(+) 463(MH⁺) 225- 230° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.20-1.34(m, 2H),1.52- 1.62(m, 3H), 1.83-1.92(m, 2H), 2.75-2.82(m, 2H), 3.25(s, 2H),3.38(s, 2H), 3.76(d, J=5.9Hz, 2H), 6.69(dd, J=1.5, 7.9Hz, 1H), 6.76(d,J=1.5Hz, 1H), 6.78- 6.83(m, 3H), 7.08-7.13(m, 2H), # 7.61(d, J=2.7Hz,1H), 7.62(d, J=2.7Hz, 1H), 9.49(br.s, 1H) 707

FAB(+) 463(MH⁺) 171- 177° C. (decom- pose) ¹H-NMR (CD₃OD) δ ppm:1.86-2.00(m, 4H), 2.76(m, 1H), 2.88-2.97(m, 2H), 3.41-3.48(m, 2H),3.52(s, 2H), 3.76(s, 3H), 4.04(s, 2H), 6.71(dd, J=1.6, 7.7Hz, 1H),6.77(d, J=1.6Hz, 1H), 6.81(m, 1H), 6.91-6.96(m, 2H), 7.12 # (d, J=7.7Hz,1H), 7.60(d, J=2.9Hz, 1H), 7.61(d, J=2.9Hz, 1H) 708

FAB(+) 413(MH⁺) 229- 230° C. (decom- pose) ¹H-NMR (DMSO-d₆) δ ppm:0.95-1.21(m, 8H), 1.33(m, 1H), 1.48-1.64(m, 3H), 1.88(m, 2H), 2.26(m,1H), 2.40(m, 2H), 2.46-2.56(m, 2H), 2.82-2.90(m, 2H), 6.24(s, 1H),6.64(d, J=7.9Hz, 1H), 6.79(d, J=7.9Hz, 1H), 7.62(d, J=2.9Hz, # 1H),7.63(d, J=2.9Hz, 1H), 9.43(s, 1H) 709

FAB(+) 389(MH⁺) 148- 152° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.38-1.49(m, 2H),1.86- 2.04(m, 4H), 2.67-2.84(m, 3H), 3.23(s, 2H), 3.27(s, 2H), 6.70(dd,J=1.5, 7.7Hz, 1H), 6.77(d, J=1.5Hz, 1H), 6.84(d, J=7.7Hz, 1H), 7.64(d,J=2.7Hz, 1H), 7.65(d, J=2.7Hz, 1H), 9.46(s, 1H) 710

¹H-NMR (CD₃OD) δ ppm: 1.42-1.56(m, 2H), 1.73- 1.82(m, 2H), 2.00-2.20(m,1H), 2.24-2.30(m, 2H), 2.84-2.88(m, 2H), 3.02— 3.08(m, 2H), 3.58(s, 2H),5.43(dd, J=6, 16Hz, 1H), 5.61-5.71(m, 1H), 6.68(s, 1H), 6.78-6.88(m,2H), 7.56(d, J=3Hz, 1H), 7.58(d, J=3Hz, 1H) 711

ESI(+) 383(MH⁺) 112- 117° C. 1H-NMR (D₂O) δ ppm: 1.35-1.45(m, 2H), 1.90-2.10(m, 5H), 2.66-2.80(m, 2H), 2.92-3.03(m, 2H), 3.13-3.23(m, 2H), 3.80-3.90(m, 2H), 6.37-6.39(m, 1H), 6.50-6.59(m, 2H), 7.19-7.26(m, 2H) 712

¹H-NMR (D₂O) δ ppm: 1.58-1.76(m, 4H), 2.65- 2.70(m, 3H), 2.74-2.82(m,2H), 3.39-3.48(m, 2H), 3.84(s, 2H), 6.35(d, J=1.6Hz, 1H), 6.51(d,J=8.0Hz, 1H), 6.56(dd, J=1.6, 8.0Hz, 1H), 7.18(d, J=2.0Hz, 1H), 7.22(d,J=2.0Hz, 1H) 713

¹H-NMR (D₂O) δ ppm: 1.44-1.54(m, 2H), 2.06(dt, J=8.0, 13.6Hz, 2H),2.59(quint, J=7.2Hz, 1H), 2.84(br.s, 2H), 3.08(br.s, 4H), 3.80(s, 2H),6.32(d, J=1.6Hz, 1H), 6.39(d, J=8.0Hz, 1H), 6.48(dd, J=1.6, 8.0Hz, 1H),7.11(d, J=3.2Hz, 1H), 7.16(d, J=3.2Hz, 1H) 714

ESI(+) 383(MH⁺) 110- 115° C. ¹H-NMR (D₂O) δ ppm: 0.82-0.95(m, 2H), 1.86-2.10(m, 5H), 2.65-2.80(m, 2H), 2.88-3.03(m, 2H), 3.07-3.23(m, 2H),3.85(s, 2H), 6.37(d, J=1.6Hz, 1H), 6.51(d, J=8.0Hz, 1H), 6.56(dd, J=1.6,8.0Hz, 1H), 7.17- 7.21(m, 1H), 7.21-7.26(m, 1H) 715

ESI(+) 383(M − Na + 2H)⁺ 203- 214° C. (decom- pose) ¹H-NMR (D₂O) δ ppm:1.60-1.72(m, 2H), 1.90- 2.15(m, 6H), 2.25-2.48(m, 1H), 3.00-3.28(m, 4H),3.85(s, {fraction (7/5)}H), 3.88(s, ⅗H), 6.34-6.39(m, 1H), 6.50-6.59(m,2H), 7.17- # 7.20(m, 1H), 7.21-7.25(m, 1H) 716

ESI(+) 423(M − Na + 2H)⁺ 231- 235° C. ¹H-NMR (D₂O) δ ppm: 1.02-1.28(m,3H), 1.36- 1.56(m, 2H), 1.62-1.84(m, 3H), 1.94-2.08(m, 2H), 2.12-2.48(m,5H), 2.56- 2.74(m, 2H), 3.35(s, 2H), 6.34(s, 1H), 6.39(s, 2H), 7.25(d,J=2.4Hz, 1H), 7.30(d, J= # 2.4Hz, 1H) 717

ESI(+) 397(M − Na + 2H)⁺ 126- 130° C. ¹H-NMR (D₂O) δ ppm: 0.63—0.90(m,2H), 1.25- 1.55(m, 5H), 1.80-2.35(m, 4H), 2.68(d, J=10.8Hz, 1H), 2.80-3.13(m, 2H), 2.88(d, J=10.4Hz, 1H), 3.68(dd, J=13.2, 22.4Hz, 2H),6.31(s, 1H), 6.38(d, J= # 8.0Hz, 1H), 6.48(d, J=8.0Hz, 1H), 7.13-7.16(m,1H), 7.16- 7.21(m, 1H) 718

ESI(+) 409(M − Na + 2H)⁺ 232- 243° C. (decom- pose) ¹H-NMR (D₂O) δ ppm:1.08-1.10(m, 2H), 1.44- 1.54(m, 1H), 1.60-2.02(m, 7H), 2.18-2.40(m, 4H),2.66(quint, J=8.8Hz, 1H), 3.09(br.s, 2H), 6.28(s, 1H), 6.31(d, J=7.6Hz,1H), 6.35(d, # J=7.6Hz, 1H), 7.25(d, J=2.8Hz, 1H), 7.31(d, J=2.8Hz, 1H)719

¹H-NMR (D₂O) δ ppm: 1.60-1.68(m, 1H), 1.73- 1.82(m, 1H), 1.88-2.03(m,4H), 2.32-2.48(m, 4H), 2.58-2.82(m, 1H), 3.12- 3.20(m, 2H), 6.21-6.26(m,1H), 6.37-6.45(m, 2H), 7.14-7.20(m, 2H) 720

¹H-NMR (DMSO-d₆) δ ppm: 1.18-1.82(m, 8H), 2.10-2.20(m, 1H), 2.28(dd,J=2.4, 8.8Hz, ⅔H), 2.34(dd, J=2.4, 8.8Hz, ⅓H), 2.44-2.57(m, 2H),2.67(dd, J=6.0, 8.8Hz, ⅓H), 2.74(dd, J=6.0, 8.8Hz, ⅔H), 3.40-3.54(m,2H), 6.70(dd, J= 1.6, 8.0Hz, ⅓H), 6.71(dd, J= # 1.6, 8.0Hz, ⅔H),6.78-6.81(m, 1H), 6.82(d, J=8.0Hz, ⅓H), 6.82(d, J=8.0Hz, ⅔H), 7.63(d,J=2.8Hz, 1H), 7.64(d, J=2.8Hz, 1H), 9.54(s, 1H) 721

ESI(+) 369(M − Na + 2H)⁺ 152- 156° C. (decom- pose) ¹H-NMR (CD₃OD) δppm: 0.50(t, J=4.8Hz, 1H), 0.60- 0.66(m, 1H), 0.96-1.04(m, 1H),1.84-2.28(m, 6H), 2.52-2.59(m, 1H), 2.78(dd, J=6.0, 11.6Hz, 1H), 3.25(d,J=13.2Hz, 1H), 3.27(d, # J=13.2Hz, 1H), 6.67(d, J=1.2Hz, 1H),6.72-6.80(m, 2H), 7.54(d, J=2.8Hz, 1H), 7.57(d, J=2.8Hz, 1H) 722

ESI(+) 411(M − Na + 2H)⁺ 226- 234° C. (decom- pose) ¹H-NMR (CD₃OD) δppm: 1.13-1.24(m, 3H), 1.28- 1.58(m, 5H), 1.66-2.10(m, 4H), 2.18-2.36(m,3H), 2.51- 2.72(m, 2H), 3.03(d, J=13.2Hz, ½H), 3.04(d, J=13.2Hz, ½H), #3.87(d, J=13.2Hz, ½H), 3.89(d, J=13.2Hz, ½H), 6.64(m, 1H), 6.72-6.80(m,2H), 7.53- 7.58(m, 2H) 723

ESI(+) 397(M − Na + 2H)⁺ 253- 265° C. (decom- pose) ¹H-NMR (CD₃OD) δppm: 1.15(d, J=6.0Hz, 1H), 1.21(d, J=6.0Hz, 2H), 1.26- 2.07(m, 9H),2.18-2.33(m, 1H), 2.57-2.71(m, 1H), 2.82-2.94(m, 1H), 3.02(d, J=13.2Hz,1H), 3.86(d, J= #13.6Hz, ⅓H), 3.87(d, J=13.2Hz, ⅔H), 6.64- 6.67(m, 1H),6.73-6.81(m, 2H), 7.53-7.58(m, 2H) 724

¹H-NMR (DMSO-d₆) δ ppm: 1.00-1.20(m, 1H), 1.30- 1.40(m, 1H),1.45-1.60(m, 1H), 1.60-1.85(m, 2H), 1.95-2.10(m, 1H), 2.30- 2.50(m, 1H),2.50-2.70(m, 1H), 2.70-2.90(m, 1H), 3.15(d, J=10Hz, 1H), 3.24(d, J=10Hz,1H), 6.65(d, J=8Hz, 1H), 6.70(s, 1H), 6.80(d, J=8Hz, 1H), 7.60(s, 2H), #9.47(s, 1H) 725

FAB(+) 383(MH⁺) ¹H-NMR (DMSO-d₆) δ ppm: 1.05-1.20(m, 2H), 1.25- 1.40(m,1H), 1.50-1.60(m, 2H), 1.75-1.90(m, 4H), 2.00-2.10(m, 2H), 3.15(s, 2H),5.70(d, J=16Hz, 1H), 6.65(d, J=8Hz, 1H), 6.75(s, 1H), 6.80(d, J=8Hz,1H), 6.82(dt, J=6, 16Hz, 1H), 7.60(s, 2H), 9.42(br.s, 1H) 726

FAB(+) 413(MH⁺) 180- 185° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.10(s, 6H),1.00-1.30(m, 5H), 1.30-1.40(m, 2H), 1.45-1.60(m, 2H), 1.75- 1.85(m, 2H),3.20(s, 2H), 3.20-3.30(m, 2H), 6.67(d, J=8Hz, 1H), 6.72(s, 1H), 6.82(d,J=8Hz, 1H), 7.60(br.s, 2H), 9.42(br.s, 1H) 727

FAB(+) 355(MH⁺) 214- 216° C. ¹H-NMR (DMSO-d₆) δ ppm: 2.24(br.m, 2H),2.42(br.s, 4H), 2.83(br.s, 2H), 3.33(s, 2H), 5.59(s, 1H), 6.72(d, J=8Hz,1H), 6.77(s, 1H), 6.85(d, J=8Hz, 1H), 7.63(s, 2H), 9.45(s, 1H),12.01(br.s, 1H) 728

FAB(+) 369(MH⁺) 125- 127° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.34(s, 3H),2.26(m, 2H), 2.34(m, 4H), 2.53(m, 2H), 3.26(s, 2H), 6.70(d, J=8Hz, 1H),6.77(s, 1H), 6.84(d, J=8Hz, 1H), 7.63(s, 2H), 9.44(s, 1H) 729

FAB(+) 399 (MH⁺), 421(M + Na⁺⁾ 149- 152° C. ¹H-NMR (DMSO-d₆) δ ppm:1.00-1.20(m, 4H), 1.14(d, J=6Hz, 3H), 1.21-1.40(m, 1H), 1.42-1.60(m,4H), 1.78-1.90(m, 2H), 2.20- 2.30(m, 1H), 2.68-2.78(m, 2H), 3.22(s, 2H),6.67(d, J=8Hz, # 1H), 6.74(s, 1H), 6.80(d, J=8Hz, 1H), 7.62(s, 2H),9.43(s, 1H) 730

FAB(+) 368(MH⁺) 128- 131° C. ¹H-NMR (DMSO-d₆) δ ppm: 2.21(m, 2H),2.38(m, 2H), 2.45(m, 2H), 2.50(m, 2H), 3.33(s, 2H), 4.43(s, 2H),6.72(dd, J=1, 8Hz, 1H), 6.77(d, J=1Hz, 1H), 6.83(d, J=8Hz, 1H), 7.63(s,2H), 9.45(br.s, 1H) 731

FAB(+) 397(MH⁺) 91- 93° C. ¹H-NMR (CD₃OD) δ ppm: 1.48(m, 1H), 1.72(m,1H), 1.81(s, 3H), 1.85-1.95(m, 3H), 2.21(m, 2H), 2.79(br.t, J=12Hz, 2H),3.35(m, 2H), 3.98(s, 2H), 6.70(t, J=7Hz, 1H), 6.74(d, J=2Hz, 1H),6.88(dd, J=2, 8Hz, 1H), 6.92(s, 1H), 6.93(d, J= # 8Hz, 1H), 7.60(s, 2H)732

98- 99° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.26-1.59(m, 5H), 1.71- 1.85(m, 2H),2.77(m, 2H), 3.22(s, 2H), 3.46(m, 1H), 6.67(d, J=8Hz, 1H), 6.75(s, 1H),6.81(d, J=8Hz, 1H), 7.61(s, 2H), 9.45(s, 1H) 733

124- 128° C. ¹H-NMR (DMSO-d₆) δ ppm: 2.11(br.s, 2H), 2.56(br.s, 1H),2.91(s, 2H), 2.94(br.s, 1H), 3.32(br.s, 4H), 5.48(s, 1H), 6.77(d, J=8Hz,1H), 6.78(s, 1H), 6.86(d, J=8Hz, 1H), 7.63(s, 2H), 9.49(br.s, 1H) 734

FAB(+) 341(MH⁺) 178- 180° C. ¹H-NMR (DMSO-d₆) δ ppm: 2.24(br.m 2H),2.43(t, J=3Hz, 2H), 2.95(br.s, 2H), 3.39(s, 2H), 6.72(d, J=4Hz, 1H),6.78(s, 1H), 6.81(br.m, 1H), 6.84(d, J=4Hz, 1H), 7.63(s, 2H), 8.33(s,1H), 9.46(s, 1H)

Example 7351-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-2,3-dehydro-3-piperidinecarboxylicacid

To a solution of 0.126 g of ethyl1-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-2,3-dehydro-3-piperidine-carboxylatein dimethyl sulfoxide (6 ml) were added in a nitrogen atmosphere 0.018 gof water and 0.448 g of tert-butoxypotassium and the resulting mixturewas reacted for 16 hours. After pouring into water, the solution wasneutralized with sodium dihyrogenphosphate. The precipitate thus formedwas taken up by filtration, washed successively with a small portion ofwater and dichloromethane and dissolved in dichloromethane. The obtainedsolution was dried over magnesium sulfate. After filtering off theinsoluble matters, the solution was concentrated to 5 ml under reducedpressure. Then diethyl ether (10 ml) was added thereto and the crystalsthus precipitated were taken up by filtration to thereby give 0.035 g ofthe title compound as pale yellow crystals.

¹H-NMR(CD₃OD) δ ppm: 1.81(quint, J=6 Hz, 2H), 2.23(t, J=6 Hz, 2H),3.19(t, J=6 Hz, 2H), 4.20(s, 2H), 6.59(d, J=1 Hz, 1H), 6.71(dd, J=1, 7Hz, 1H), 6.85(d, J=7 Hz, 1H), 7.57(d, J=3 Hz, 1H), 7.57(d, J=3 Hz, 1H),7.58(1H, s)

MS: FAB(+)340(MH⁺⁾

m.p.: 158-160° C.

Example 736N-[1-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-piperidin-4-yl)sulfamoylaceticacid

To a solution of (2-trimethylsilylethyl)N-[1-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)piperidin-4-yl)sulfamoylacetatein tetrahydrofuran (30 ml) was added in a nitrogen atmosphere at 0° C.5.4 ml of a 1 M solution of tetra-n-butylammonium fluoride intetrahydrofuran and the resulting mixture was stirred at 0° C. for 1hour and then at room temperature for 2 hours. The reaction mixture wasconcentrated under reduced pressure and the residue was purified byHigh-porous gel chromatography (CHP20P, mfd. by Mitsubishi ChemicalIndustries, 45-150μ) (eluted with methanol/water). The compound thusobtained was dissolved again in a 5 N aqueous solution of sodiumhydroxide (100 ml) and washed with dichloromethane. Then the aqueouslayer was neutralized with sodium dihydrogenphosphate and treated byHigh-porous gel chromatography (CHP20P, mfd by Mitsubishi ChemicalIndustries, 75-150μ) (eluted with methanol/water) again. Thus 0.190 g ofthe title compound was obtained as pale yellow crystals.

¹H-NMR(CD₃OD) δ ppm: 1.55-1.62(m, 4H), 1.98(d, J=10 Hz, 2H), 2.15(d,J=10 Hz, 2H), 2.81(d, J=10 Hz, 1H), 3.2(m, 1H), 3.35(s, 2H), 3.85(s,2H), 6.66(d, J=1 Hz,. 1H), 6.76(dd, J=1, 8 Hz, 1H), 6.80(d, J=8 Hz, 1H),7.55(d, J=3 Hz, 1H), 7.57(d, J=3 Hz, 1H)

MS: FAB(+)436(MH⁺)

m.p.: 200-210° C.

Examples 737 to

The following compounds were obtained by the same method as the one ofExample 8.

Ex. Structural formula MS M.p. NMR 737

FAB (+) 385 (MH+) 218- 220° C. ¹H-NMR (DMSO-d₆) δ ppm: 0.82 (d, J = 6.8Hz, 3H), 1.48-1.55 (m, 3H), 1.69-1.95 (m, 5H), 2.24- 2.30 (m, 2H),2.75-2.82 (m, 2H), 3.22 (s, 2H), 6.67 (d, J = 8.0 Hz, 1H), 6.75 (s, 1H),6.81 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 2.8 Hz, 1H), 7.63 (d, J = 2.8 Hz,1H), 9.43 (s, 1H) 738

ESI (+) 419 (MH⁺) >297° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.78-1.90 (m, 2H),2.14-2.26 (m, 2H), 2.36- 2.46 (m, 2H), 2.68-2.80 (m, 2H), 3.30-3.40 (m,2H), 6.73 (d, J = 8 Hz, 1H), 6.76 (s, 1H), 6.84 (d, J = 8 Hz, 1H), 7.24(t, J = 7 Hz, 1H), 7.33 (t, J = 7 Hz, 2H), 7.37 (d, J = 7 Hz, 2H), 7.62(d, J = 2 Hz, 1H), 7.63 (d, J = 2 Hz, 1H), 9.46 (s, 1H) 739

FAB (+) 499 (MH⁺) >295° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.70-1.90 (m, 2H),2.10-2.20 (m, 2H), 2.30- 2.45 (m, 2H), 2.60-2.80 (m, 2H), 3.30 (m, 2H),3.71 (s, 3H), 6.68-6.74 (m, 1H), 6.76 (d, J = 2 Hz, 1H), 6.84 (d, J = 8Hz, 1H), 6.88 (d, J = 9 Hz, 2H), 7.28 (d, J = 9 Hz, 2H), 7.62 (d, J = 3Hz, 1H), 7.63 (d, J = 3 Hz, 1H), 9.45 (s, 1H) 740

FAB (+) 435 (MH⁺) 260- 262° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.60-1.80 (m,2H), 1.90-2.12 (m, 2H), 2.20- 2.40 (m, 2H) 2.54-2.72 (m, 2H), 3.23 (m,2H), 6.69 (d, J = 8 Hz, 1H), 6.69 (d, J = 9 Hz, 2H), 6.75 (s, 1H), 6.82(d, J = 8 Hz, 1H), 7.15 (d, J = 9 Hz, 2H), 7.62 (s, 2H), 9.32 (s, 1H),9.42 (s, 1H) 741

ESI (+) 371 (MH⁺) 262- 264° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.46-1.66 (m,4H), 1.70-1.80 (m, 2H), 1.84- 1.96 (m, 2H), 2.10-2.20 (m, 1H), 2.21 (t,J = 7 Hz, 2H), 2.38 (t, J = 8 Hz, 2H), 2.7-2.8 (m, 2H), 6.60 (s, 1H),6.62 (d, J = 8 Hz, 1H), 6.78 (d, J = 8 Hz, 1H), 7.60 (d, J = 3 Hz, 1H),7.62 (d, J = 3 Hz, 1H), 9.41 (s, 1H) 742

FAB (+) 427 (MH⁺) 275- 280° C. ¹H-NMR (DMSO-d₆) δ ppm: 0.93-1.08 (m,2H), 1.02 (d, J = 8 Hz, 3H), 1.13-1.23 (m, 2H), 1.28- 1.40 (m, 1H),1.40-1.76 (m, 4H), 2.21-2.32 (m, 1H), 2.58-2.73 (m, 1H), 2.86-3.01 (m,1H), 3.50- 3.65 (m, 1H), 4.27-4.43 (m, 1H), 6.71 (d, J = 1.7 Hz, 1H),6.74 (dd, J = 1.7, 7.7 Hz, 1H), 6.94 (d, J = 7.7 Hz, 1H), 7.64 (d, J =2.9 #Hz, 1H), 9.58 (s, 1H) 743

FAB (+) 400 (MH⁺) 115- 118° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.01 (d, J = 7.1Hz, 3H), 1.03-1.22 (m, 5H), 1.25-1.37 (m, 1H), 1.44- 1.55 (m, 1H),1.55-1.66 (m, 2H), 1.78-2.01 (m, 2H), 2.18-2.29 (m, 1H), 2.68-2.83 (m,2H), 3.32 (s, 2H), 6.94 (br.d, J = 1.9 Hz, 1H), 7.63 (s, 2H), 7.69(br.d, J = 1.9 Hz, 1H), 9.49-9.60 (br.s, 1H) 744

FAB (+) 372 (MH⁺) 148- 152° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.38-1.54 (m,2H), 1.80-1.90 (m, 2H), 2.40- 2.50 (m, 1H), 2.60-2.70 (m, 2H), 3.10-3.22(m, 2H), 3.14 (s, 2H), 3.51 (s, 2H), 6.74 (d, J = 8.0 Hz, 1H), 6.75 (s,1H), 6.81 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 2.8 Hz, 1H), 7.62 (d, J =2.8 Hz, 1H), 9.45 (s, 1H) 745

FAB (+) 400 (MH⁺) 185- 191° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.45-1.53 and1.53- 1.61 (m, total 2H), 1.63- 1.79 (m, total 2H), 2.01 and 2.14 (s,total 3H), 2.40- 2.49 (m, total 2H), 2.981- 3.08 (m, total 2H), 3.09 and3.10 (s, total 2H), 3.68- 3.82 and 4.24-4.38 (m, total 1H), 4.28 and4.35 (s, 2H), 6.61 and 6.65 (dd, J = 1.7, 8.0 Hz, total 1H), 6.62 and6.70 (d, J = 1.7 Hz, #total 1H), 6.80 and 6.88 (d, J = 8.0 Hz, total1H), 7.61 and 7.62 (d, J = 3.0 Hz, total 1H), 7.62 and 7.63 (d, J = 3.0Hz, total 1H), 9.44 and 9.49 (s, total 1H) 746

FAB (+) 450 (MH⁺) 210- 215° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.52-1.70 (m,4H), 1.86-1.98 (m, 2H), 2.72- 2.80 (m, 2H), 3.08 (s, 3H), 3.23 (s, 2H),3.38-3.48 (m, 1H), 3.68 (s, 2H), 6.66 (d, J = 8.0 Hz, 1H), 6.75 (s, 1H),6.81 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 2.8 Hz, 1H), 7.62 (d, J = 2.8 Hz,1H), 9.44 (s, 1H) 747

FAB (+) 415 (MH⁺) 207- 210° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.20-1.35 (m,3H), 1.66-1.75 (m, 2H), 1.94- 2.04 (m, 2H), 2.60-2.69 (m, 2H), 3.24 (s,2H), 3.64 (d, J = 5.6 Hz, 2H), 5.93 (t, J = 5.6 Hz, 1H), 6.10 (d, J =7.2 Hz, 1H), 6.68 (d, J = 8.0 Hz, 1H), 6.74 (s, 1H), 6.82 (d, J = 8.0Hz, 1H), 7.61 (d, J = 2.8 Hz, 1H), 7.63 (d, J = 2.8 Hz, 1H), 9.43 (s,1H) 748

FAB (+) 442 (MH⁺) 94-98° C. ¹H-NMR (DMSO-d₆) δ ppm: 0.85-1.00 (m, 2H),1.02 (d, J = 6.0 Hz, 3H), 1.10-1.22 (m, 3H), 1.26- 1.40 (m, 2H),1.50-1.62 (m, 2H), 2.20-2.32 (m, 1H), 2.55-2.65 (m, 2H), 3.85-3.95 (m,2H), 4.02 (d, J = 5.2 Hz, 2H), 6.62-6.68 (m, 1H), 6.65 (s, 1H), 6.81 (d,J = 8.0 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 2.8 Hz, 1H),7.63 #(d, J = 2.8 Hz, 1H), 9.51 (s, 1H) 749

FAB (+) 450 (MH⁺) 185- 189° C. (de- compose) ¹H-NMR (DMSO-d₆) δ ppm:1.32-1.45 (m, 3H), 1.82-1.90 (m, 2H), 2.57- 2.70 (m, 2H), 2.80 (s, 3H),3.15 (s, 2H), 3.44-3.56 (m, 2H), 3.62 (s, 2H), 6.74 (d, J = 8.0 Hz, 1H),6.78 (d, J = 8.0 Hz, 1H), 6.79 (s, 1H), 7.59 (d, J = 2.8 Hz, 1H), 7.61(d, J = 2.8 Hz, 1H), 9.45 (s, 1H) 750

FAB (+) 428 (MH⁺) 240- 242° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.05 (s, 6H),1.26- 1.35 (m, 2H), 1.38-1.42 (m, 2H), 2.18 (t, J = 7 Hz, 2H), 2.30(br.s, 8H), 3.23 (s, 2H), 6.68 (dd, J = 1, 8 Hz, 1H), 6.74 (d, J = 1 Hz,1H), 6.83 (d, J = 8 Hz, 1H), 7.62 (d, J = 3 Hz, 1H), 7.63 (d, J = 3 Hz,1H), 9.44 (s, 1H) 751

FAB (+) 428 (MH⁺) >275° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.06 (s, 6H), 1.43(m, 2H), 1.65 (m, 2H), 3.05 (br.s, 2H), 3.44 (br.s, 4H), 3.50 (br.s,4H), 4.16 (s, 2H), 6.86 (br.s, 1H), 6.98 (d, J = 8 Hz, 1H), 7.12 (br.d,J = 8 Hz, 1H), 7.64 (d, J = 3 Hz, 1H), 7.65 (d, J = 3 Hz, 1H), 9.70 (s,1H)

Examples

The following compounds were obtained by the same method as the one ofExample 9.

Ex. Structural formula MS M.p. NMR 752

FAB (+) 357 (MH⁺), 379 (MNa⁺) 142- 146° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.05-1.25 (m, 2H), 1.50-1.65 (m, 3H), 1.83- 1.90 (m, 2H), 2.03 (d, J = 6 Hz,2H), 2.70-2.75 (m, 2H), 3.22 (s, 2H), 6.66 (d, J = 8 Hz, 1H), 6.74 (s,1H), 6.80 (d, J = 8 Hz, 1H), 7.62 (s, 2H), 9.40 (s, 1H) 753

FAB (+) 433 (MH⁺) 158- 161° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.10- 1.19 (m,2H), 1.19-1.30 (m, 3H), 1.50- 1.70 (m, 2H), 2.40-2.52 (m, 2H), 2.50-2.60 (m, 2H), 3.30 (s, 2H), 6.64 (s, 2H), 6.83 (s, 1H), 7.26 (d, J = 8Hz, 2H), 7.63 (s, 2H), 7.82 (d, J = 8 Hz, 2H), 9.50 (s, 1H) 754

FAB (+) 384 (MH⁺) ¹H-NMR (DMSO-d₆) δ ppm: 1.00- 1.30 (m, 5H), 1.40-1.55(m, 2H), 1.55- 1.62 (m, 2H), 1.70-1.90 (m, 2H), 2.12 (t, J = 6 Hz, 2H),2.70-2.80 (m, 2H), 3.22 (s, 2H), 6.65 (d, J = 8 Hz, 1H), 6.73 (s, 1H),6.80 (d, J = 8 Hz, 1H), 7.60 (s, 2H), 9.43 (br.s, 1H) 755

FAB (+) 343 (MH⁺) ¹H-NMR (DMSO-d₆) δ ppm: 1.40- 1.60 (m, 2H), 1.65-1.80(m, 2H), 1.80- 1.95 (m, 2H), 2.0-2.13 (m, 1H), 2.60- 2.75 (m, 2H), 3.20(s, 2H), 6.66 (d, J = 8 Hz, 1H), 6.78 (s, 1H), 6.82 (d, J = 8 Hz, 1H),7.62 (s, 2H), 9.43 (br.s, 1H)

Example 756[5-[1-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)piperidin-4-yl]-2-hydroxy-3-oxo-2-methyl-4-pentan-5-yl]thioaceticacid

To a solution of 0.240 g of[5-[1-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)piperidin-4-yl]-2-hydroxy-2-methyl-4-penten-3-onein tetrahydrofuran (20 ml) was added at 0° C. a solution of 0.18 g ofmercaptoacetic acid in water (10 ml). After adding 0.18 g of sodiumhydroxide, the resulting mixture was stirred at room temperature for 30minutes and then concentrated under reduced pressure. Next, the residuewas purified by High-porous gel chromatography (CHP20P, mfd byMitsubishi Chemical Industries, 75-150μ) (eluted with methanol/water) tothereby give 0.165 g of the title compound as pale yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 1.15(s, 6H), 1.18-1.23(m, 1H), 1.36-1.46(m, 2H),1.53(br.d, J=13 Hz, 1H), 1.61(br.d, J=13 Hz, 1H), 1.74-1.83(m, 2H),2.78(d, J=11 Hz, 2H), 2.87-2.98(m, 2H), 3.08(m, 1H), 3.17(d, J=4 Hz,2H), 3.22(s, 2H), 6.67(d, J=8 Hz, 1H), 6.75(d, J=2 Hz, 1H), 6.82(dd,J=2, 8 Hz, 1H), 7.62(m, 2H), 9.42(s, 1H)

MS: FAB(+)503(MH⁺)

m.p.: 130-132° C.

Example 757[1-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-1-azoniabicyclo[2.2.2]octane-4-carboxylate

0.620 g of 1-azabicyclo[2.2.2]octane-4-carboxylic acid was dissolved in40 ml of acetonitrile. After adding 3.98 g ofN-methyl-N-(trimethylsilyl)trifluoroacetamide, the resulting mixture wasstirred for 2 hours. Next, 0.998 g of8-chloromethyl-10H-pyrazino[2,3-b][1,4]benzothiazine was added theretoand the resulting mixture was heated under reflux for 4 hours. Afterdistilling off the solvent under reduced pressure, the residue wasdissolved in methanol/dichloromethane. After adding diethyl ether, themixture was filtered and the residue was purified by High-porous gelchromatography (CHP20P, mfd by Mitsubishi Chemical Industries, 75-150μ)(eluted with methanol/water) to thereby give 0.21 g of the titlecompound as a yellow powder.

¹H-NMR(DMSO-d₆) δ ppm: 2.19(t, J=8 Hz, 6H), 3.43(t, J=8 Hz, 6H), 4.19(s,2H), 6.71(d, J=2 Hz, 1H), 6.88(dd, J=2, 8 Hz, 1H), 6.99(d, J=8 Hz, 1H),7.62(s, 2H)

MS: FAB(+)369(MH⁺)

m.p.: 229-230° C.

Example 758[1-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)piperidin-4-yl]oxyaceticacid

Ethyl(piperidin-4-yl)oxyacetate was treated by the same methods as thoseof Examples 63 and 18 to thereby give the title compound as yellowcrystals.

¹H-NMR(DMSO-d₆) δ ppm: 1.35-1.47(m, 2H), 1.76-1.84(m, 2H), 1.95-2.06(m,2H), 2.56-2.64(m, 2H), 3.24(s, 2H), 3.29-3.38(m, 1H), 3.98(s, 2H),6.68(dd, J=1.8, 7.8 Hz, 1H), 6.74(d, J=1.8 Hz, 1H), 6.82(d, J=7.8 Hz,1H), 7.61(d, J=2.8 Hz, 1H), 7.62(d, J=2.8 Hz, 1H), 9.43(s, 1H)

MS: ESI(+)373(MH+)

m.p.: 204-207° C.

Example 759[1-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-piperidin-4-yl]methylthioaceticacid

Ethyl[1-(tert-butoxycarbonyl)piperidin-4-yl)methylthio-acetate wastreated successively by the same methods as those of Examples 66 and 18to thereby give the title compound.

¹H-NMR(DMSO-d₆) δ ppm: 1.10-1.20(m, 2H), 1.36-1.48(m, 1H), 1.63-1.72(m,2H), 1.82-1.91(m, 2H), 2.48(d, J=7.2 Hz, 2H), 2.71-2.78(m, 2H), 3.17(s,2H), 3.24(s, 2H), 6.68(d, J=7.9 Hz, 1H), 6.74(s, 1H), 6.82(d, J=7.9 Hz,1H), 7.62(s, 2H), 9.43(s, 1H)

MS: FAB(+)403(MH⁺)

m.p.: 110-113° C.

Example 7608-[2-[(1,3-Dithiacyclohexan-2-ylidene)methyl]-4,5,6,7-tetrahydro-6H-thieno[2,3-c]pyridin-6-ylmethyl]-10H-pyrazino[2,3-b][1,4]benzothiazine

2-[(1,3-Dithiacyclohexan-2-ylidene)methyl]-6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-6H-thieno[2,3-c]pyridinewas treated by the same method as the one of Example 66 to thereby givethe title compound as orange crystals.

¹H-NMR(CDCl₃) δ ppm: 2.20(quint, J=6.0 Hz, 2H), 2.72(br.t, J=5.4 Hz,2H), 2.84(br.t, J=5.4 Hz, 2H), 2.98(t, J=6.0 Hz, 2H), 3.00(t, J=6.0 Hz,2H), 3.60(s, 2H), 3.70(br.s, 2H), 6.51-6.58(br.s, 1H), 6.68(br.d, J=1.6Hz, 1H), 6.77(s, 1H), 6.79(dd, J=1.6, 8.0 Hz, 1H), 6.85(d, J=8.0 Hz,1H), 6.92(s, 1H), 7.57(d, J=2.8 Hz, 1H), 7.68(d, J=2.8 Hz, 1H)

Example 761[6-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-4,5,6,7-tetrahydro-6H-thieno[2,3-c]pyridin-2-yl]aceticacid

8-[2-[(1,3-Dithlacyclohexan-2-ylidene)methyl]-4,5,6,7-tetrahydro-6H-thieno[2,3-c]pyridin-6-ylmethyl]-10H-pyrazino[2,3-b][1,4]benzothiazinewas treated successively by the same methods as those of ProductionExample 63 and Example 18 to thereby give the title compound as yellowcrystals.

¹H-NMR(DMSO-d₆) δ ppm: 2.56(t, J=6.8 Hz, 2H), 2.65(t, J=6.8 Hz, 2H),3.47(s, 4H), 3.64(s, 2H), 6.59(s, 1H), 6.73(d, J=8.0 Hz, 1H), 6.81(s,1H), 6.84(d, J=8.0 Hz, 1H), 7.61 (d, J=2.8 Hz, 1H), 7.62(d, J=2.8 Hz,1H), 9.45(s, 1H)

MS: FAB(+)411(MH⁺)

m.p.: 98-105° C.

Example 7624-[1-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-yl]acetyl]-piperidin-4-yl]-2-methylbutanoicacid

10-(Methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine-8-acetic acidwas treated successively by the same methods as those of Examples 362,18 and 8 to thereby give the title compound as yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 0.82-0.94(m, 2H), 1.01(d, J=7.1 Hz, 3H),1.10-1.19(m, 2H), 1.26-1.46(m, 2H), 1.46-1.56(m, 1H), 1.56-1.66(m, 2H),2.19-2.30(m, 1H), 2.43-2.53(m, 1H), 2.86-2.96(m, 1H), 3.50(s, 2H),3.82(br.d, J=13.0 Hz, 1H), 4.33(br.d, J=13 Hz, 1H), 6.62(s, 1H), 6.63(d,J=8.3 Hz, 1H), 6.82(d, J=8.3 Hz, 1H), 7.62(d, J=2.7 Hz, 1H), 7.63(d,J=2.7 Hz, 1H), 9.48(s, 1H)

MS: FAB(+)427(MH⁺)

m.p.: 84-89° C.

Production Example 1202-[N-Methyl-(2-nitrophenyl)amino]-3-chloropyrazine

To a solution of 1.52 g of N-methyl-2-nitroaniline inN,N-dimethylformamide (50 ml) was added in a nitrogen atmosphere 0.44 gof sodium hydride. After stirring for 30 minutes, 1.75 g of2,3-dichloropyrazine was added thereto and the resulting mixture wasstirred at room temperature for additional 6 hours. Then the reactionmixture was distributed into ethyl acetate and a saturated aqueoussolution of sodium dihydrogenphosphate and the aqueous layer wasextracted with ethyl acetate. The organic layers were combined, washedsuccessively with water and a saturated aqueous solution of sodiumchloride and dried over anhydrous magnesium sulfate. After distillingoff the solvent under reduced pressure, the residue was purified bysilica gel column chromatography (eluted with n-hexane/ethyl acetate) tothereby give 0.586 g of the title compound as an oily substance.

¹H-NMR(CDCl₃) δ ppm: 3.45(s, 3H), 7.08(dd, J=1, 7 Hz, 1H), 7.39(dt, J=1,7 Hz, 1H), 7.58(dt, J=1, 7 Hz, 1H), 7.89(d, J=2 Hz, 1H), 7.97(dd, J=1, 7Hz, 1H), 8.17(d, J=2 Hz, 1H)

Production Example 121 2-[(2-Nitrophenyl)amino]-3-chloropyrazine

Starting with 41.4 g of 2-nitroaniline and 35.0 g of2,3-dichloropyrazine, 39.8 g of the title compound was obtained by thesame method as the one described in Production Example 120.

¹H-NMR(CDCl₃) δ ppm: 7.13(dt, J=1, 7 Hz, 1H), 7.67(dt, J=1, 7 Hz, 1H),7.96(d, J=2 Hz, 1H), 8.18(d, J=2 Hz, 1H), 8.31(dd, J=1,7 Hz, 1H),9.02(dd, J=1, 7 Hz, 1H), 11.00(br.s, 1H)

Production Examples

The following compounds were obtained from various anilines and2,3-dichloropyrazine by the same procedure as the one of ProductionExample 121.

Prodn. Ex. Structural formula NMR 122

¹H-NMR (CDCl₃) δ ppm: 3.50 (s, 3H), 5.22 (s, 2H), 7.39 (dd, J = 3, 9 Hz,1H), 7.91 (d, J = 3 Hz, 1H), 7.95 (d, J = 3 Hz, 1H), 8.12 (d, J = 3 Hz,1H), 8.88 (d, J = 9 Hz, 1H), 10.70 (br.s, 1H) 123

¹H-NMR (CDCl₃) δ ppm: 3.87 (s, 3H), 7.28 (dd, J = 3, 10 Hz, 1H), 7.75(d, J = 3 Hz, 1H), 7.90 (d, J = 3 Hz, 1H), 8.12 (d, J = 3 Hz, 1H), 8.88(d, J = 10 Hz, 1H), 10.70 (br.s, 1H) 124

¹H-NMR (CDCl₃) δ ppm: 1.42 (t, J = 7 Hz, 3H), 4.42 (q, J = 7 Hz, 2H),8.14 (d, J = 3 Hz, 1H), 8.24 (d, J = 3 Hz, 1H), 8.29 (dd, J = 2, 8 Hz,1H), 8.98 (d, J = 2 Hz, 1H), 9.16 (d, J = 8 Hz, 1H), 11.30 (s, 1H) 125

¹H-NMR (CDCl₃) δ ppm: 7.87 (dd, J = 2, 8 Hz, 1H), 8.10 (d, J = 3 Hz,1H), 8.26 (d, J = 3 Hz, 1H), 8.65 (d, J = 2 Hz, 1H), 9.30 (d, J = 8 Hz,1H), 11.34 (s, 1H) 126

¹H-NMR (CDCl₃) δ ppm: 7.90 (dd, J = 2, 8 Hz, 1H), 7.98 (d, J = 3 Hz,1H), 8.18 (d, J = 3 Hz, 1H), 8.60 (d, J = 2 Hz, 1H), 8.84 (d, J = 8 Hz,1H), 10.95 (br.s, 1H)

Production Example 127 2-[(2-Aminophenyl)amino]-3-chloropyrazine

To a solution of 1.1 g of 2-[(2-nitrophenyl)-1-amino)]-3-chloropyrazinein tetrahydrofuran (35 ml) was added an aqueous solution (14 ml) of 7 gof sodium hydrosulfide. After adding 14 ml of 50% aqueous ammoniathereto, the resulting mixture was vigorously stirred at roomtemperature for 16 hours. Then the reaction mixture was distributed intoethyl acetate and water and the organic layer was dried over anhydrousmagnesium sulfate. After distilling off the solvent under reducedpressure, the residue was purified by silica gel column chromatography(eluted with n-hexane/ethyl acetate) to thereby give 0.28 g of the titlecompound as yellow crystals.

¹H-NMR(CDCl₃) δ ppm: 3.73(br.s, 2H), 6.79(br.s, 1H), 6.83-6.87(m, 2H),7.10(t, J=7 Hz, 1H), 7.38(d, J=7 Hz, 1H), 7.74(d, J=2 Hz, 1H), 8.00(d,J=2 Hz, 1H)

Production Examples

The following compounds were obtained by reducing nitro groups by thesame procedure as the one of Production Example 127.

Prodn. Ex. Structural formula NMR 128

¹H-NMR (CDCl₃) δ ppm: 3.48 (s, 3H), 3.79 (br.s, 2H), 5.14 (s, 2H), 6.51(dd, J = 3, 8 Hz, 1H), 6.54 (br.s, 1H), 6.56 (d, J = 3 Hz, 1H), 7.14 (d,J = 8 Hz, 1H), 7.70 (d, J = 3 Hz, 1H), 7.98 (d, J = 3 Hz, 1H) 129

¹H-NMR (CDCl₃) δ ppm: 3.78 (s, 3H), 3.80 (br.s, 2H), 6.37-6.40 (m, 2H),6.53 (br.s, 1H), 7.12 (d, J = 9 Hz, 1H), 7.69 (d, J = 3 Hz, 1H), 7.98(d, J = 3 Hz, 1H) 130

¹H-NMR (CDCl₃) δ ppm: 1.39 (t, J = 7 Hz, 3H), 3.69 (br.s, 2H), 4.35 (q,J = 7 Hz, 2H), 7.20 (br.s, 1H), 7.58-7.62 (m, 2H), 7.80 (d, J = 3 Hz,1H), 7.81 (d, J = 8 Hz, 1H), 8.06 (d, J = 3 Hz, 1H) 131

¹H-NMR (CDCl₃) δ ppm: 3.75 (br.s, 2H), 7.14 (d, J = 2 Hz, 1H), 7.17(br.s, 1H), 7.20 (dd, J = 2, 8 Hz, 1H), 7.85 (d, J = 3 Hz, 1H), 7.90 (d,J = 8 Hz, 1H), 8.08 (d, J = 3 Hz, 1H)

Production Example 132 2-[N-Allyl-(2-nitrophenyl)amino]-3-chloropyrazine

A solution of 5.01 g of 2-[(2-nitrophenyl)amino]-3-chloropyrazine inN,N-dimethylformamide (200 ml) was degassed in a nitrogen atmosphere andthen 0.92 g of sodium hydride (60% oily) was added thereto at 0° C.After stirring for 30 minutes, 4.84 g of allyl bromide was added and theresulting mixture was stirred at ordinary temperature for 16 hours. Thenthe reaction mixture was distributed into ethyl acetate and water andthe aqueous layer was extracted with ethyl acetate. The organic layerswere combined, washed successively with water and a saturated aqueoussolution of sodium chloride and dried over anhydrous magnesium sulfate.After distilling off the solvent under reduced pressure, the residue waspurified by silica gel column chromatography (eluted with n-hexane/ethylacetate) to thereby give 4.78 g of the title compound as a colorlessoily substance.

¹H-NMR(CDCl₃) δ ppm: 4.54(d, J=7 Hz, 2H), 5.11-5.16(m, 2H), 5.99-6.09(m,1H), 7.19(dd, J=1, 7 Hz, 1H), 7.38(dt, J=1, 7 Hz, 1H), 7.57(dt, J=1, 7Hz, 1H), 7.91(d, J=3 Hz, 1H), 7.95(dd, J=1, 7 Hz, 1H), 8.16(d, J=3 Hz,1H)

Production Examples

The following compounds were obtained by treating2-[(2-nitrophenyl)amino]-3-chloropyrazine with various halides by thesame procedure as the one of Production Example 132.

Prodn. Ex. Structural formula NMR 133

¹H-NMR (CDCl₃) δ ppm: 1.45 (s, 9H), 4.40 (s, 2H), 7.45 (dt, J = 2, 8 Hz,1H), 7.51 (dd, J = 2, 8 Hz, 1H), 7.60 (dt, J = 2, 8 Hz, 1H), 7.91 (d, J= 2 Hz, 1H), 8.03 (dd, J = 2, 8 Hz, 1H), 8.12 (d, J = 2 Hz, 1H) 134

¹H-NMR (CDCl₃) δ ppm: 3.88 (s, 3H), 5.22 (s, 2H), 7.11 (dd, J = 1, 7 Hz,1H), 7.37 (dt, J = 1, 7 Hz, 1H), 7.42 (d, J = 8 Hz, 2H), 7.51 (dt, J =1, 7 Hz, 1H), 7.91-7.94 (m, 4H), 8.12 (d, J = 3 Hz, 1H) 135

¹H-NMR (CDCl₃) δ ppm: 3.71 (s, 3H), 4.66 (d, J = 6 Hz, 2H), 5.93 (d, J =16 Hz, 1H), 7.10 (td, J = 6, 16 Hz, 1H), 7.14 (d, J = 8 Hz, 1H), 7.42(t, J = 8 Hz, 1H), 7.57 (t, J = 8 Hz, 1H), 7.95 (s, 1H), 7.97 (d, J = 8Hz, 1H), 8.17 (s, 1H)

Production Examples

The following compounds were obtained by the same method as the one ofProduction Example 132 by replacing the allyl bromide by methyl iodide.

Prodn. Ex. Structural formula NMR 136

¹H-NMR (CDCl₃) δ ppm: 3.42 (s, 3H), 3.50 (s, 3H), 5.23 (s, 2H), 7.10 (d,J = 9 Hz, 1H), 7.24 (dd, J = 3, 9 Hz, 1H), 7.65 (s, 1H), 7.85 (s, 1H),8.15 (d, J = 3 Hz, 1H) 137

¹H-NMR (CDCl₃) δ ppm: 3.42 (s, 3H), 3.88 (s, 3H), 7.05 (m, 2H), 7.49 (m,1H), 7.84 (d, J = 3 Hz, 1H), 8.15 (d, J = 3 Hz, 1H) 138

¹H-NMR (CDCl₃) δ ppm: 1.41 (t, J = 7 Hz, 3H), 3.51 (s, 3H), 4.42 (q, J =7 Hz, 2H), 7.25 (d, J = 8 Hz, 1H), 8.02 (d, J = 2 Hz, 1H), 8.20 (d, J =2 Hz, 1H), 8.21 (dd, J = 2, 8 Hz, 1H), 8.58 (d, J = 2 Hz, 1H) 139

¹H-NMR (CDCl₃) δ ppm: 3.53 (s, 3H), 7.33 (d, J = 8 Hz, 1H), 7.83 (dd, J= 2, 8 Hz, 1H), 8.12 (d, J = 3 Hz, 1H), 8.20 (d, J = 2 Hz, 1H), 8.21 (d,J = 3 Hz, 1H) 140

¹H-NMR (CDCl₃) δ ppm: 3.37 (s, 3H), 6.86 (d, J = 8 Hz, 1H), 7.80 (d, J =8 Hz, 1H), 7.88 (s, 1H), 8.12 (s, 1H), 8.19 (s, 1H)

Production Examples

The following compounds were obtained by the same method as the one ofProduction Example 132 by replacing the allyl bromide by chloromethylmethyl ether.

Prodn. Ex. Structural formula NMR 141

¹H-NMR (CDCl₃) δ ppm: 3.38 (s, 3H), 3.50 (s, 3H), 5.23 (s, 2H), 5.27 (s,2H), 7.26 (d, J = 9 Hz, 1H), 7.32 (d, J = 9 Hz, 1H), 7.62 (s, 1H), 7.94(s, 1H), 8.18 (s, 1H) 142

¹H-NMR (CDCl₃) δ ppm: 3.39 (s, 3H), 3.88 (s, 3H), 5.27 (s, 2H), 7.14(dd, J = 3, 9 Hz, 1H), 7.33 (d, J = 9 Hz, 1H), 7.46 (d, J = 3 Hz, 1H),7.94 (d, J = 3 Hz, 1H), 8.18 (d, J = 3 Hz, 1H) 143

¹H-NMR (CDCl₃) δ ppm: 3.35 (s, 3H), 5.39 (s, 2H), 7.75 (d, J = 8 Hz,1H), 7.87 (d, J = 2, 8 Hz, 1H), 8.15 (d, J = 2 Hz, 1H), 8.17 (d, J = 3Hz, 1H), 8.25 (d, J = 3 Hz, 1H) 144

¹H-NMR (CDCl₃) δ ppm: 3.38 (s, 3H), 5.32 (s, 2H), 7.42 (dt, J = 1, 8 Hz,1H), 7.47 (dd, J = 1, 8 Hz, 1H), 7.62 (dt, J = 1, 8 Hz, 1H), 7.94 (dd, J= 1, 8 Hz, 1H), 8.00 (d, J = 2 Hz, 1H), 8.21 (d, J = 2 Hz, 1H)

Production Example 145(E)-2-[N-(4-Bromo-2-buten-1-yl)-N-(2-nitrophenyl)amino]-3-chloropyrazine

Similar to Production Example 132, 5.04 g of2-[(2-nitrophenyl)amino]-3-chloropyrazine was treated with(E)-1,4-dibromo-2-butene to thereby give 0.34 g of the title compound.

¹H-NMR(CDCl₃) δ ppm: 3.86(d, J=7 Hz, 2H), 4.51(d, J=6 Hz, 2H), 5.76(td,J=7, 14 Hz, 1H), 6.01(td, J=6, 14 Hz, 1H), 7.15(dd, J=1, 8 Hz, 1H),7.41(dt, J=1, 8 Hz, 1H), 7.57(dt, J=1, 8 Hz, 1H), 7.92(d, J=2 Hz, 1H),7.97(dd, J=l, 8 Hz, 1H), 8.17(d, J=2 Hz, 1H)

Production Example 146(E)-2-[N-(4-Dimethylamino-2-buten-1-yl)-N-(2-nitrophenyl)amino]-3-chloropyrazine

Similar to Example 1094, 0.34 g of(E)-2-[N-(4-bromo-2-buten-1-yl)-N-(2-nitrophenyl)amino]-3-chloropyrazinewas treated with 20 ml of a 0.86 M ethanol solution of dimethylamine in5 ml of ethanol to thereby give 0.17 g of the title compound as a yellowoily substance.

¹H-NMR(CDCl₃) δ ppm: 2.65(s, 6H), 3.57(d, J=7 Hz, 2H), 4.53(d, J=6 Hz,2H), 5.90(td, J=7, 16 Hz, 1H), 6.16(td, J=6, 16 Hz, 1H), 7.17(dd, J=1, 8Hz, 1H), 7.41(dt, J=1, 8 Hz, 1H), 7.60(dt, J=1, 8 Hz, 1H), 7.92(dd, J=1,8 Hz, 1H), 7.93(d, J=2 Hz, 1H), 8.19(d, J=2 Hz, 1H)

Production Example 1473-[[N-(3-Chloropyrazin-2-yl)-N-(2-nitrophenyl)]amino]-1,2-propanediol

1.16 g of 2-[N-[allyl-N-(2-nitrophenyl)amino]-3-chloropyrazine wastreated in the same manner as that of Example 1195 to thereby give 0.716g of the title compound.

¹H-NMR(CDCl₃) δ ppm: 3.55-3.60(m, 1H), 3.62-3.68(m, 1H), 3.93(br.s, 1H),3.98-4.03(m, 1H), 4.08-4.20(m, 2H), 4.43(br.s, 1H), 7.36(d, J=7 Hz, 1H),7.45(t, J=7 Hz, 1H), 7.63(t, J=7 Hz, 1H), 7.98(d, J=2 Hz, 1H), 8.00(d,J=7 Hz, 1H), 8.14(d, J=2 Hz, 1H)

Production Example 148 2-(6-Methyl-2-nitrophenyl)thio-3-chloropyrazine

To a solution of 1.254 g of 6-methyl-2-nitrobenzenethiol intetrahydrofuran (10 ml) was added 0.326 g of sodium hydride underice-cooling in a nitrogen atmosphere. After stirring for 10 minutes,1.67 g of dichloropyrazine was added thereto and the resulting mixturewas stirred at room temperature for 1 hour and heated under reflux for1.5 hour. Then the reaction mixture was poured into a saturated aqueoussolution of sodium dihydrogenphosphate and extracted with ethyl acetate.The organic layer was dried over anhydrous magnesium sulfate anddistilled under reduced pressure. Then the residue was purified bysilica gel column chromatography (eluted with n-hexane/ethyl acetate) tothereby give 0.737 g of the title compound as a red oily substance.

¹H-NMR(CDCl₃) δ ppm: 2.46(s, 3H), 7.53(t, J=8 Hz, 1H), 7.58(dd, J=2, 8Hz, 1H), 7.68(dd, J=2, 8 Hz, 1H), 8.06(d, J=3 Hz, 1H), 8.10(d, J=3 Hz,1H)

Production Example 149 Diethyl 2-phenyl-2-(5-nitropyridin-2-yl)malonate

14.9 g of diethyl phenylmalonate was dissolved in 50 ml ofN,N-dimethylformamide and 2.52 g of sodium hydride (60% oily) was addedthereto at room temperature. Next, 5.0 g of 2-chloro-5-nitropyridine wasadded thereto and the resulting mixture was stirred at 80° C. for 2hours. After the completion of the reaction, the reaction mixture waspoured into ice-water/ethyl acetate and neutralized with dilutehydrochloric acid. After extracting with ethyl acetate, the extract wasdried over anhydrous sodium sulfate and filtered. The filtrate wasdistilled under reduced pressure and the obtained residue was purifiedby silica gel column chromatography (eluted with ethyl acetate/n-hexane)to thereby give 16.55 g of the title compound as a reddish brown oilysubstance.

¹H-NMR(CDCl₃) δ ppm: 1.23(t, J=7 Hz, 6H), 4.15(q, J=7 Hz, 4H),7.20-7.45(m, 6H), 8.25(d, J=7 Hz, 1H), 9.38(s, 1H)

Production Example 150 2-Benzyl-5-nitropyridine

1.5 g of diethyl 2-phenyl-2-(5-nitropyridin-2-yl)malonate was dissolvedin 50 ml of ethanol. After adding 10 ml of water and 10 ml of conc.sulfuric acid, the mixture was heated under reflux for 8 hours. Afterthe completion of the reaction, the reaction mixture was poured into asaturated aqueous solution of sodium hydrogencarbonate and extractedwith ethyl acetate. The extract was dried over anhydrous sodium sulfateand filtered. The filtrate was distilled under reduced pressure and theobtained residue was purified by silica gel column chromatography(eluted with ethyl acetate/n- hexane) to thereby give 632 mg of thetitle compound as reddish brown crystals.

¹H-NMR(CDCl₃) δ ppm: 4.28(s, 2H), 7.20-7.43(m, 6H), 8.33(d, J=7 Hz, 1H),9.36(s, 1H)

Production Example 151 2-Benzyl-5-aminopyridine

389 mg of 2-benzyl-5-nitropyridine was dissolved in ethyl acetate and153 mg of 10% palladium carbon was added thereto. Then the resultingmixture was stirred under a hydrogen gas stream at room temperatureunder atmospheric pressure for 30 minutes. Then the reaction mixture wasfiltered through celite. After distilling off the solvent under reducedpressure, 333 mg of the title compound was obtained as an amber oilysubstance.

¹H-NMR(CDCl₃) δ ppm: 3.65(br.s, 2H), 4.02(s, 2H), 6.82(d, J=7 Hz, 1H),6.85(d, J=7 Hz, 1H), 7.13-7.36(m, 5H), 7.97(s, 1H)

Production Examples

The following compounds were obtained by successively treating diethylbenzylmalonate and diethyl methylmalonate in the same manner as those ofProduction Examples 149, 150 and 151.

Prodn. Ex. Structural formula NMR 152

¹H-NMR (CDCl₃) δ ppm: 2.92 (s, 4H), 3.90 (br.s, 2H), 6.72-6.83 (m, 2H),7.08-7.20 (m, 2H), 7.20-7.30 (m, 3H), 7.96 (br.s, 1H) 153

¹H-NMR (CDCl₃) δ ppm: 1.23 (t, J = 7 Hz, 3H), 2.72 (q, J = 7 Hz, 2H),3.58 (br.s, 2H), 6.92 (s, 2H), 8.00 (s, 1H)

Production Example 154 Triethyl5-methyl-1-(5-nitropyridin-2-yl)hexane-1,1,5-tricarboxylate

5 g of diethyl malonate was dissolved in 30 ml of N,N-dimethylformamideand 1.550 g of sodium hydride (60% oily) was added thereto underice-cooling. Next, 7.04 g of ethyl 2,2-dimethyl-5-bromopentanoate wasadded to the reaction mixture and the resulting mixture was stirred at80° C. for 2 hours. After ice-cooling the reaction mixture again, 1.550g of sodium hydride (60% oily) was added thereto. After stirring for 25minutes, 7.4 g of 2-chloro-5-nitropyridine was added and the resultingmixture was stirred at 80° C. for 1.5 hours. After the completion of thereaction, the reaction mixture was poured into a saturated aqueoussolution of sodium chloride and repeatedly extracted with ethyl acetate.The extracts were dried over anhydrous sodium sulfate and filtered. Thefiltrate was distilled under reduced pressure and the obtained residuewas purified by silica gel column chromatography (eluted with ethylacetate/n-hexane) to thereby give 9.71 g of the title compound as ayellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.12(s, 6H), 1.13(t, J=7 Hz, 3H), 1.14(t, J=7 Hz,6H), 1.43-1.60(m, 2H), 2.25-2.38(m, 4H), 4.10(q, J=7 Hz, 2H), 4.21(q,J=7 Hz, 2H), 4.23(q, J=7 Hz, 2H), 8.00(d, J=8 Hz, 1H), 8.49(d, J=8 Hz,1H), 9.33(s, 1H)

Production Example 155 Ethyl6-(5-nitropyridin-2-yl)-2,2-dimethylhexanoate

9.71 g of triethyl5-methyl-1-(5-nitropyridin-2-yl)hexane-1,1,5-tricarboxylate was treatedin the same manner as the one of Production Example 149 to thereby give2.87 g of a yellow oily substance. A 1.82 g portion of this product wasdissolved in 30 ml of ethanol. After adding 3 ml of conc. sulfuric acid,the resulting mixture was heated under reflux for 7 hours. After thecompletion of the reaction, the reaction mixture was poured into asaturated aqueous solution of sodium chloride and extracted with ethylacetate. The extract was dried over anhydrous sodium sulfate andfiltered. The filtrate was distilled under reduced pressure and theobtained residue was purified by silica gel column chromatography(eluted with ethyl acetate/n-hexane) to thereby give 1.0 g of the titlecompound as a yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.12(s, 6H), 1.22(t, J=7 Hz, 3H), 1.60-1.80(m, 4H),2.30(t, J=6 Hz, 2H), 2.60(t, J=6 Hz, 2H), 4.13(q, J=7 Hz, 2H), 7.35(d,J=8 Hz, 1H), 8.37(dd, J=2, 8 Hz, 1H), 9.28(d, J=2 Hz, 1H)

Production Example 156 6-(5-Nitropyridin-2-yl)-2,2-dimethylhexanamide

Ethyl 6-(5-nitropyridin-2-yl)-2,2-dimethylhexanoate was treated in thesame manner as the one of Example 18 and 661 mg of6-(5-nitropyridin-2-yl)-2,2-dimethylhexanoic acid thus obtained wasdissolved in 15 ml of tetrahydrofuran. After adding 695 mg ofcarbonyldiimidazole, the resulting mixture was heated under reflux for 2hours. Then the reaction mixture was cooled to room temperature and 25ml of saturated aqueous ammonia was added thereto followed by stirringover day and night. After the completion of the reaction, the reactionmixture was poured into a saturated aqueous solution of sodium chlorideand repeatedly extracted with ethyl acetate. The extracts were driedover anhydrous sodium sulfate and filtered. The filtrate was distilledunder reduced pressure and the residue was purified by silica gel columnchromatography (eluted with toluene/acetone) to thereby give 453 mg ofthe title compound as white crystals.

¹H-NMR(CDCl₃) δ ppm: 1.13(s, 6H), 1.30-1.40(m, 2H), 1.50-1.60(m, 2H),1.70-1.80(m, 2H), 2.90(t, J=7 Hz, 2H), 5.55-5.80(br.s, 2H), 7.16(d, J=7Hz, 1H), 8.37(d, J=7 Hz, 1H), 9.33(s, 1H)

Production Examples

Ethyl 6-(5-nitropyridin-2-yl)-2,2-dimethylhexanoate and6-(5-nitropyridin-2-yl)-2,2-dimethylhexanamide were hydrogenated in thesame manner as the one of Production Example 151 to thereby give thefollowing compounds.

Prodn. Ex. Structural formula NMR 157

¹H-NMR (CDCl₃) δ ppm: 1.13 (s, 6H), 1.23 (t, J = 7 Hz, 3H), 1.60-1.80(m, 4H), 2.32 (t, J = 6 Hz, 2H), 2.60 (t, J = 6 Hz, 2H), 3.40-3.60(br.s, 2H), 4.12 (q, J = 7 Hz, 2H), 6.92 (s, 2H), 8.01 (s, 1H) 158

¹H-NMR (CDCl₃) δ ppm: 1.13 (s, 6H), 1.22-1.36 (m, 2H), 1.50-1.58 (m,2H), 1.60-1.70 (m, 2H), 2.63 (t, J = 7 Hz, 2H), 3.60 (br.s, 2H), 5.62(br.s, 2H), 6.92 (s, 2H), 7.99 (s, 1H)

Production Example 159 Mixture of 2-methyl-5-aminopyridine withethyl(5-aminopyridin-2-yl)acetate

3.131 g of diethyl 2-(5-nitropyridin-2-yl)malonate, 476 mg of lithiumchloride and 0.2 ml of water were dissolved in 10 ml ofN,N-dimethylformamide and heated at 120° C. for 3 hours. Then thereaction mixture was distilled under reduced pressure and the residuethus obtained was purified by silica gel column chromatography (elutedwith ethyl acetate/n-hexane) to thereby give 803 mg of a mixture of2-methyl-5-nitropyridine with ethyl(5-nitropyridin-2-yl)acetate as areddish brown crystalline substance. 803 mg of these crystals werehydrogenated in the same manner as the one of Production Example 151 tothereby give as a pale yellow oily substance 614 mg of a mixture of thetitle compounds which could be hardly separated.2-methyl-5-aminopyridine:

¹H-NMR(CDCl₃) δ ppm: 2.27(s, 3H), 3.70-3.90(br.s, 2H), 6.82(d, J=2 Hz,1H), 6.98(d, J=7 Hz, 1H), 7.93(dd, J=2, 7 Hz, 1H)ethyl(5-aminopyridin-2-yl)acetate

¹H-NMR(CDCl₃) δ ppm: 1.18(t, J=7 Hz, 3H), 3.65(s, 2H), 3.70-3.90(br.s,2H), 4.10(q, J=7 Hz, 2H), 6.82(d, J=2 Hz, 1H), 6.98(d, J=7 Hz, 1H),7.93(dd, J=2, 7 Hz, 1H)

Production Example 160 N-(Imidazol-2-ylmethyl)acetamide

0.34 g of 2-aminomethylimidazole dihydrochloride was added to 20 ml ofN,N-dimethylformamide in a nitrogen atmosphere. Under ice-cooling, 0.40g of sodium hydride (60% oily) was added thereto and the resultingmixture was subjected to ultrasonication for 30 minutes. To the reactionmixture were added 20 ml of pyridine and 10 ml of acetic anhydride andthe obtained mixture was stirred at room temperature for 2 days. Afterconcentrating under reduced pressure, the residue was distributed intowater and ethyl acetate. The organic layer was washed with water anddried over anhydrous sodium sulfate. The extract was concentrated underreduced pressure to thereby give 0.24 g of the title compound as a palebrown solid.

¹H-NMR(CDCl₃) δ ppm: 1.99(s, 3H), 4.44(d, J=7 Hz, 2H), 6.96(s, 2H),8.25(br.s, 1H), 8.39(br.m, 1H)

Production Example 161N-[1-[2-(Trimethylsilyl)ethoxymethyl]imidazol-2-ylmethyl]-acetamide

Under ice-cooling, 0.08 g of sodium hydride (60% oily) was added to asolution of 0.31 g of N-(imidazol-2-ylmethyl)acetamide inN,N-dimethylformamide (10 ml). After stirring for 15 minutes, a solutionof 0.35 ml of 2-(trimethylsilyl)ethoxymethyl chloride inN,N-dimethylformamide (1 ml) was dropped thereinto and the resultingmixture was stirred at room temperature for additional 16 hours. Thenthe reaction mixture was distributed into water and ethyl acetate. Theorganic layer was washed with water and dried over anhydrous magnesiumsulfate. After concentrating under reduced pressure, the residue waspurified by silica gel column chromatography (eluted withdichloromethane/methanol) to thereby give 0.16 g of the title compoundas a colorless oily substance.

¹H-NMR(CDCl₃) δ ppm: 0.01(s, 9H), 0.92(t, J=8 Hz, 2H), 2.05(s, 3H),3.51(t, J=8 Hz, 2H), 4.54(d, J=7 Hz, 2H), 5.30(s, 2H), 6.53(br.s, 1H),6.99(d, J=1 Hz, 1H), 7.01(d, J=1 Hz, 1H)

Production Example 162 2-[N-(tert-Butoxycarbonyl)aminomethyl]imidazole

To an aqueous solution (10 ml) of 0.34 g of 2-aminomethylimidazoledihydrochloride were added 0.32 g of sodium hydroxide and 0.34 g ofsodium hydrogencarbonate. Then a tetrahydrofuran solution (10 ml) of1.05 g of di-tert-butyl dicarbonate was added thereto and the resultingmixture was stirred at room temperature for 16 hours. After adding anaqueous solution of disodium hydrogenphosphate, the resulting mixturewas extracted with ethyl acetate. The organic layer was washedsuccessively with water and a saturated aqueous solution of sodiumchloride and dried over anhydrous magnesium sulfate. After concentratingunder reduced pressure, the residue was purified by silica gel columnchromatography (eluted with n-hexane/ethyl acetate) to thereby give 0.20g of the title compound as a colorless powder.

¹H-NMR(CDCl₃) δ ppm: 1.43(s, 9H), 4.32(d, J=7 Hz, 2H), 5.43(br.s, 1H),6.96(s, 2H)

Production Example 1631-[2-(Trimethylsilyl)ethoxymethyl-2-[N-(tert-butoxycarbonyl)-aminomethyl]imidazole

Starting with 2-[N-(tert-butoxycarbonyl)aminomethyl]-imidazole, thetitle compound was obtained by the same procedure as that of ProductionExample 161.

¹H-NMR(CDCl₃) δ ppm: 0.01(s, 9H), 0.92(t, J=8 Hz, 2H), 1.46(s, 9H),3.49(t, J=8 Hz, 2H), 4.46(d, J=5 Hz, 2H), 5.33(br.s, 2H), 7.00(br.s,2H), 8.03(br.s, 1H)

Production Example 164N,N-Dimethyl-[2-[(pyridin-2-yl)hydroxymethyl]imidazol-1-yl]-sulfonamide

To a solution of 4.37 g of 2-bromopyridine in diethyl ether (40 ml) wasadded 16.5 ml of a 1.6 M hexane solution of n-butyllithium at −78° C. ina nitrogen atmosphere. After stirring for 30 minutes, a tetrahydrofuransolution (20 ml) of 4.34 g ofN,N-dimethyl-2-formylimidazole-1-sulfonamide was added thereto. Then thereaction mixture was brought back to room temperature and distributedinto ethyl acetate and an aqueous solution of ammonium chloride. Theorganic layer was extracted and washed successively with water and asaturated aqueous solution of sodium chloride and dried over anhydroussodium sulfate. After distilling off the solvent under reduced pressure,the residue was purified by silica gel column chromatography (elutedwith dichloromethane/methanol) to thereby give 2.02 g of the titlecompound as a pale yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 2.99(s, 6H), 5.32(d, J=7 Hz, 1H), 6.30(d, J=7 Hz,1H), 7.00(d, J=1 Hz, 1H), 7.29(d, J=1 Hz, 1H), 7.26-7.31(m, 2H),7.71(dt, J=2, 8 Hz, 1H), 8.61(dt, J=1, 5 Hz, 1H

Production Example 165[(Pyridin-2-yl)[1-(N,N-dimethylsulfonamido)imidazol-1-yl]methyl acetate

0.93 g ofN,N-dimethyl-[2-[(pyridin-2-yl)hydroxymethyl]-imidazol-1-yl]-sulfonamidewas dissolved in 20 ml of pyridine and 1.0 ml of acetic anhydride and0.44 g of 4-dimethylaminopyridine were added thereto. After stirring atroom temperature for 48 hours, the solvent was distilled off underreduced pressure. Then the residue was purified by silica gel columnchromatography (eluted with dichloromethane/methanol) to thereby give0.976 g of the title compound as an orange oily substance.

¹H-NMR(CDCl₃) δ ppm: 2.20(s, 3H), 3.00(s, 6H), 7.08(d, J=2 Hz, 1H),7.22(s, 1H), 7.25(ddd, J=2, 5, 8 Hz, 1H), 7.30(d, J=2 Hz, 1H),7.40(br.d, J=8 Hz, 1H), 7.73(dt, J=2, 8 Hz, 1H), 8.58(ddd, J=1, 2, 5 Hz,1H)

Production Example 166N,N-Dimethyl[2-(pyridin-2-ylmethyl)imidazol-1-yl]sulfonamide

A solution of 0.97 g of[(pyridin-2-yl)[1-(N,N-dimethylsulfonamido)imidazol-1-yl]methyl acetatein ethanol (30 ml) was stirred in the presence of 0.20 g of palladiumcarbon (containing 50% of moisture) in a hydrogen gas stream at roomtemperature for 20 hours. After filtering off the catalyst, the residuewas concentrated under reduced pressure to thereby give 0.21 g of thetitle compound as a colorless oily substance.

¹H-NMR(CDCl₃) δ ppm: 2.81(s, 6H), 4.54(s, 2H), 7.03(d, J=2 Hz, 1H),7.16(ddd, J=1, 5, 8 Hz, 1H), 7.21(br.d, J=8 Hz, 1H), 7.28(d, J=2 Hz,1H), 7.64(dt, J=2, 8 Hz, 1H), 8.54(ddd, J=1, 2, 5 Hz, 1H)

Production Example 167 2-(Pyridin-2-ylmethyl)imidazole

To a solution of 0.21 g ofN,N-dimethyl[2-(pyridin-2-ylmethyl)imidazol-1-yl]sulfonamide in ethanol(2 ml) was added a 2% aqueous solution (20 ml) of potassium hydroxideand the resulting mixture was heated under reflux for 11 hours. Afterdistilling off the solvent under reduced pressure, the residue waspurified by silica gel column chromatography (eluted withdichloromethane/methanol) to thereby give 0.053 g of the title compoundas a colorless oily substance.

¹H-NMR(CDCl₃) δ ppm: 4.22(s, 2H), 7.02(s, 2H), 7.13(ddd, J=1, 5, 8 Hz,1H), 7.25(br.d, J=8 Hz, 1H), 7.59(dt, J=2, 8 Hz, 1H), 8.51(ddd, J=1, 2,5 Hz, 1H)

Production Example 168 2-Pyridyl 2-imidazolyl ketone

To an ethanol solution (5 ml) of 1.41 g ofN,N-dimethyl[2-(pyridin-2-yl)hydroxymethyl)imidazol-1-yl]sulfonamide wasadded 50 ml of a 2% aqueous solution of potassium hydroxide and theresulting mixture was heated under reflux for 9 hours. After distillingoff the solvent under reduced pressure, the residue was purified bysilica gel column chromatography (eluted with dichloromethane/methanol)to thereby give 0.441 g of the title compound as a colorless oilysubstance.

¹H-NMR(CDCl₃) δ ppm: 7.32(br.s, 1H), 7.47(br.s, 1H), 7.58(ddd, J=2, 5, 8Hz, 1H), 7.98(dt, J=2, 8 Hz, 1H), 8.46(br.d, J=8 Hz, 1H), 8.76(br.d, J=5Hz, 1H)

Production Example 169N,N-Dimethyl-2-[[4-(4,4-dimethyl-2-oxazolin-2-yl)phenyl]hydroxymethyl]imidazole-1-sulfonamide

Similar to Production Example 164, 4.54 g ofN,N-dimethyl-2-formylimidazole-1-sulfonamide was treated with 7.0 g of2-(4-bromophenyl)-4,4-dimethyl-2-oxazoline to thereby give 3.41 g of thetitle compound.

¹H-NMR(CDCl₃) δ ppm: 1.36(s, 6H), 2.72(s, 6H), 3.98(d, J=7 Hz, 1H),4.08(s, 2H), 6.21(d, J=7 Hz, 1H), 7.08(d, J=2 Hz, 1H), 7.24(d, J=2 Hz,1H), 7.41(d, J=8 Hz, 2H), 7.91(d, J=8 Hz, 2H)

Production Example 170 Methyl 4-[(imidazol-2-yl)carbonyl]benzoate andmethyl 4-[(imidazol-2-yl)hydroxymethyl]benzoate

To a solution of 1.70 g ofN,N-dimethyl-2-[[4-(4,4-dimethyl-2-oxazolin-2-yl)phenyl]hydroxymethyl]imidazole-1-sulfonamidein ethanol was added 50 ml of a 2% aqueous solution of potassiumhydroxide and the resulting mixture was heated under reflux for 15hours. After distilling off the solvent under reduced pressure, 50 ml ofmethanol and 5 ml of conc. sulfuric acid were added to the residue andthe resulting mixture was heated under reflux for 10 hours. Afterdistilling off methanol under reduced pressure, the residue wasdistributed into ethyl acetate and an aqueous solution of sodiumbicarbonate. The organic layer was extracted, washed successively withwater and a saturated aqueous solution of sodium chloride and dried overanhydrous sodium sulfate. After distilling off the solvent under reducedpressure, the residue was purified by silica gel column chromatography(eluted with dichloromethane/methanol) to thereby give 0.38 g of methyl4-[(imidazol-2-yl)carbonyl]benzoate and 0.21 g of methyl4-[(imidazol-2-yl)hydroxymethyl]benzoate each as a colorless oilysubstance.

methyl 4-[(imidazol-2-yl)carbonyl]benzoate

¹H-NMR(CDCl₃) δ ppm: 3.89(s, 3H), 7.27(d, J=1 Hz, 1H), 7.35(d, J=1 Hz,1H), 8.11(d, J=8 Hz, 2H), 8.57(d, J=8 Hz, 2H)

methyl 4-[(imidazol-2-yl)hydroxymethyl]benzoate

¹H-NMR(CDCl₃) δ ppm: 3.91(s, 3H), 5.98(s, 1H), 6.99(s, 2H), 7.50(d, J=8Hz, 2H), 8.02(d, J=8 Hz, 2H)

Production Example 171 Methyl4-[(1-acetylimidazol-2-yl)acetoxymethyl]benzoate

To a pyridine solution (16 ml) of 0.21 g of methyl4-[(imidazol-2-yl)hydroxymethyl]benzoate was added 0.5 ml of aceticanhydride and the resulting mixture was stirred at room temperature for20 hours. After distilling off the solvent under reduced pressure, 0.25g of the title compound was obtained as an orange oily substance.

¹H-NMR(CDCl₃) δ ppm: 2.15(s, 3H), 2.54(s, 3H), 3.79(s, 3H), 7.06(s, 1H),7.23(s, 1H), 7.35(s, 1H), 7.56(d, J=8 Hz, 2H), 8.02(d, J=8 Hz, 2H)

Production Example 172 Methyl 4-[(imidazol-2-yl)methyl]benzoate

0.25 g of methyl 4-[(1-acetylimidazol-2-yl)acetoxy-methyl]benzoate wastreated in the same manner as the one of Production Example 166 tothereby give the title compound.

¹H-NMR(CDCl₃) δ ppm: 3.90(s, 3H), 4.17(s, 2H), 6.99(s, 2H), 7.32(d, J=8Hz, 2H), 7.99(d, J=8 Hz, 2H)

Production Example 173 8-Trifluoromethyl-6-dimethylaminopurine

0.306 g of 4,5-diamino-6-dimethylaminopyrimidine was dissolved in 20 mlof trifluoroacetic anhydride. Then the reaction mixture was introducedinto a steel container. After sealing, it was heated to 100° C. for 14hours. The reactor was opened at room temperature and the solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography (eluted with n-hexane/ethyl acetate) tothereby give 0.073 g of the title compound as white crystals.

¹H-NMR(CDCl₃) δ ppm: 3.47(br.s, 3H), 3.99(br.s, 3H), 8.39(s, 1H)

Production Example 174 6-Dimethylamino-8-oxo-7(H),8(H)-purine

To an acetonitrile solution (30 ml) of 0.306 g of4,5-diamino-6-dimethylaminopyrimidine was added 30 ml of an acetonitrilesolution of 0.512 g of N,N′-disuccinimidyl carbonate and the resultingmixture was stirred for 24 hours. Further, 0.256 g ofN,N′-disuccinimidyl carbonate was added thereto and the resultingmixture was stirred at room temperature for 24 hours. Next, the reactionmixture was concentrated under reduced pressure and the crystals thusprecipitated were collected by filtration and washed successively withwater and methanol. Thus 0.128 g of the title compound was obtained asbrown crystals.

¹H-NMR(CDCl₃) δ ppm: 3.08(s, 6H), 7.99(s, 1H), 10.54(br.s, 1H),11.34(br.s, 1H)

Production Example 175 (Purin-6-yl)ethanone

1.04 g of 6-(ethoxyvinyl)purine was dissolved in 80 ml of 1 Nhydrochloric acid and stirred at room temperature for 15 hours. Afterneutralizing with a saturated aqueous solution of sodium bicarbonate, itwas extracted with dichloromethane and the organic layer was dried overanhydrous sodium sulfate. After distilling off the solvent under reducedpressure, 0.70 g of crude title compound was obtained as a colorlessoily substance.

¹H-NMR(DMSO-d₆) δ ppm: 2.75(s, 3H), 8.80(s, 1H), 9.14(s, 1H)

Production Example 176 1-(Purin-6-yl)ethanol

To an ethanol solution (80 ml) of 0.70 g of (purin-6-yl)ethanone wasadded 0.70 g of sodium borohydride and the resulting mixture was stirredat room temperature for 4 hours. The excessive reagent was decomposed byadding water and 4 N hydrochloric acid and distilled off under reducedpressure. The residue was purified by silica gel column chromatography(eluted by dichloromethane/methanol) to thereby give 0.57 g of the titlecompound as a white solid.

¹H-NMR(CDCl₃) δ ppm: 1.48(d, J=7 Hz, 3H), 5.05(m, 1H), 5.78(br.s, 1H),8.58(s, 1H), 8.82(s, 1H)

Production Example 177 6-[1-(tert-Butyldimethylsiloxy)ethyl]purine

To a solution of 0.543 g of 1-(purin-6-yl)ethanol inN,N-dimethylformamide (10 ml) were added 0.27 g of imidazole and 0.598 gof tert-butyldimethylsilyl chloride and the resulting mixture wasstirred at room temperature for 15 hours. After distilling off thesolvent under reduced pressure, the residue was purified by silica gelcolumn chromatography (eluted with dichloromethane/methanol) to therebygive 0.793 g of the title compound as a white solid.

¹H-NMR(CDCl₃) δ ppm: 0.08(s, 3H), 0.01(s, 3H), 0.77(s, 9H), 1.53(d, J=7Hz, 3H), 5.23(q, J=7 Hz, 1H), 8.37(s, 1H), 9.03(s, 1H)

Example 763 5,10-Dihydro-5-methyl-10H-pyrazino[2,3-b][1,4]quinoxaline

To a solution of 0.586 g of2-[N-methyl-N-(2-nitro-phenyl)amino]-3-chloropyrazine in tetrahydrofuran(20 ml) was added 4 g of hydrosulfite sodium in water (8 ml). Afteradding 8 ml of 50% aqueous ammonia/water, the resulting mixture wasvigorously stirred at room temperature for 6 hours. Then the reactionmixture was distributed into ethyl acetate and water and the organiclayer was dried over anhydrous magnesium sulfate. After distilling offthe solvent under reduced pressure, the residue was purified by silicagel column chromatography (eluted with n-hexane/ethyl acetate) tothereby give 0.32 g of the title compound as yellow crystals.

¹H-NMR(CDCl₃) δ ppm: 2.93(s, 3H), 6.33(m, 1H), 6.42(m, 1H), 6.50-6.56(m,2H), 6.83(d, J=3 Hz, 1H), 6.93(d, J=3 Hz, 1H), 9.04(s, 1H)

m.p.: 229-231° C.

MS: FAB(+)198(M⁺)

Example 764 5,10-Dihydro-10H-pyrazino[2,3-b][1,4]quinoxaline

A solution of 0.28 g of 2-[(2-aminophenyl)amino]-3-chloropyrazine inN,N-dimethylformamide (15 ml) was degassed and then heated to 100° C.for 30 minutes. Next, the reaction mixture was brought back to roomtemperature and poured into water. The precipitate was taken up byfiltration and dissolved in 2 N hydrochloric acid. After filtering offthe insoluble matters, the hydrochloric acid solution was neutralizedwith potassium hydroxide. The crystals thus precipitated were taken upby filtration to thereby give 0.10 g of the title compound as greenishyellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 6.23(dd, J=3, 6 Hz, 2H), 6.39(dd, J=3, 6 Hz, 2H),6.75(s, 2H), 8.75(s, 2H)

m.p.: 215-217° C.

MS: FAB(+)184(M⁺)

Example 765 5,10-Dihydro-5-allyl-10H-pyrazino[2,3-b][1,4]quinoxaline

2.91 g of 2-[N-allyl-N-(2-nitrophenyl)amino]-3-chloropyrazine wastreated by the same method as the one of Example 985 to thereby give1.26 g of the title compound as a yellow powder.

¹H-NMR(CDCl₃) δ ppm: 4.28(d, J=5 Hz, 2H), 5.23(d, J=11 Hz, 1H), 5.30(d,J=16 Hz, 1H), 5.79-5.91(tdd, J=5, 11, 16 Hz, 1H), 6.21(d, J=8 Hz, 1H),6.36(d, J=8 Hz, 1H), 6.54-6.63(m, 2H), 6.91(d, J=3 Hz, 1H), 7.04(d, J=3Hz, 1H)

m.p.: 173-175° C.

MS: ESI(+)225(MH⁺)

Examples

The following compounds were obtained by reacting analogs of2-[(2-nitrophenyl)amino]-3-chloropyrazine by the same method as the oneof Example 763.

Ex. Structural formula MS M.p. NMR 766

ESI (+) 299 (MH⁺) 199-201° C. ¹NMR(CDCl₃) δ ppm: 1.40(s, 9H), 4.25(s,2H), 6.13-6.15(m, 1H), 6.17-6.19(m, 1H), 6.52- 6.58(m, 2H), 6.91(d,J=3Hz, 1H), 6.99(d, J=3Hz, 1H) 767

ESI (+) 333 (MH⁺) 232-234° C. ¹NMR(CDCl₃) δ ppm: 3.90(s, 3H), 4.96(br ·s, 2H), 6.15(dd, J=1, 8Hz, 1H), 6.24(dd, J=1, 8Hz, 1H), 6.48(dt, J=1,8Hz, 1H), 6.57(dt, J=1, 8Hz, 1H), 6.98(d, J=3Hz, 1H), 7.04(d, J=3Hz,1H), 7.41(d, J=8Hz, 2H), 8.01(d, J=8Hz, 2H) 768

ESI (+) 287 (MH⁺) 195-197° C. ¹NMR(CDCl₃) δ ppm: 3.72(s, 3H), 4.44(m,2H), 6.06(d, J=16Hz, 1H), 6.24(m, 2H), 6.60(m, 2H), 6.95- 7.05(m, 3H)769

ESI (+) 229 (MH⁺) 185-188° C. ¹NMR(CDCl₃) δ ppm: 3.45(s, 3H), 5.13(s,2H), 6.14(br · s, 1H), 6.26(m, 1H), 6.65- 6.71(m, 3H), 7.05(d, J=3Hz,1H), 7.13(d, J=3Hz, 1H) 770

ESI (+) 275 (MH⁺) 194-196° C. ¹NMR(CDCl₃) δ ppm: 4.85(s, 2H), 6.13-6.17(m, 2H), 6.41(dt, J=2, 8Hz, 1H), 6.48(dt, J=2, 8Hz, 1H), 6.87(d,J=3Hz, 1H), 6.97(d, J=3Hz, 1H), 7.16-7.28(m, 5H), 7.46(br · s, 1H) 771

ESI (+) 281 (MNa⁺) 191-194° C. ¹NMR(CDCl₃) δ ppm: 3.34(m, 2H), 3.53-3.64(m, 2H), 3.71- 3.76(m, 1H), 4.64(t, J=6Hz, 1H), 4.90(d, J=6Hz, 1H),6.29-6.31(m, 1H), 6.46-6.52(m, 2H), 6.55-6.59(m, 1H), 6.81(d, J=3Hz,1H), 6.87(d, J=3Hz, 1H), 9.02(s, 1H)

Examples

The following compounds were obtained by reacting analogs of2-[1-(2-amino-4-substituted phenyl)amino]-3-chloropyrazine by the samemethod as the one of Example 764.

Ex. Structural formula MS M.p. NMR 772

FAB (+) 244 (MH⁺) ¹NMR(CDCl₃) δ ppm: 3.38(s, 3H), 4.94(s, 2H), 6.03(s,1H), 6.07(d, J=8Hz, 1H), 6.15(d, J=8Hz, 1H), 6.74(m, 2H), 8.65(s, 1H),8.79(s, 1H) 773

¹NMR(CDCl₃) δ ppm: 3.54(s, 3H), 5.92(d, J=2Hz, 1H), 5.99(dd, J=2, 8Hz,1H), 6.17(d, J=8Hz, 1H), 6.74(d, J=3Hz, 1H), 6.76(d, J=3Hz, 1H), 8.64(s,1H), 8.77(s, 1H) 774

ESI (+) 257 (MH⁺) >275° C. ¹NMR(DMSO-d₆) δ ppm: 1.21(t, J=7Hz, 3H),4.16(q, J=7Hz, 2H), 6.26(d, J=8Hz, 1H), 6.79-6.85(m, 3H), 7.05(dd, J=1,8Hz, 1H), 8.94(s, 1H), 9.23(s, 1H) 775

EI (+) 209 (M⁺) >275° C. ¹NMR(DMSO-d₆) δ ppm: 6.26(d, J=8Hz, 1H),6.37(d, J=1Hz, 1H), 6.83-6.88(m, 3H), 9.05(s, 1H), 9.30(s, 1H)

Examples

The following compounds were obtained by reacting analogs of2-[(nitrophenyl)amino]-3-chloropyrazine by the same method as the one ofExample 763.

Ex. Structural formula MS M.p. NMR 776

ESI (+) 228 (M⁺) 198-201° C. ¹NMR(CDCl₃) δ ppm: 3.06(s, 3H), 3.68(s,3H), 5.87(d, J=1Hz, 1H), 6.17(dd, J=1, 8Hz, 1H), 6.31(d, J=8Hz, 1H),6.54(br · s, 1H), 6.89(d, J=3Hz, 1H), 7.08(d, J=3Hz, 1H) 777

ESI (+) 259 (MH⁺) 197-198° C. ¹NMR(CDCl₃) δ ppm: 2.92(s, 3H), 3.32(s,3H), 4.98(s, 2H), 6.11(d, J=2Hz, 1H), 6.21(dd, J=2, 8Hz, 1H), 6.34(d,J=8Hz, 1H), 6.83(d, J=3Hz, 1H), 6.95(d, J=3Hz, 1H), 9.07(s, 1H) 778

ESI (+) 224 (MH⁺) 274-275° C. ¹NMR(DMSO-d₆) δ ppm: 2.94(s, 3H), 6.45(d,J=2Hz, 1H), 6.48(d, J=8Hz, 1H), 6.95(d, J=3Hz, 1H), 6.98(dd, J=2, 8Hz,1H), 7.01(d, J=3Hz, 1H), 9.33(s, 1H) 779

ESI (+) 271 (MH⁺) 239-242° C. ¹NMR(DMSO-d₆) δ ppm: 1.23(t, J=7Hz, 3H),2.96(s, 3H), 4.18(q, J=7Hz, 2H), 6.47(d, J=8Hz, 1H), 6.86(d, J=2Hz, 1H),6.91(d, J=3Hz, 1H), 6.99(d, J=3Hz, 1H), 7.16(dd, J=2, 8Hz, 1H), 9.20(s,1H) 780

ESI (+) 325 (MH⁺) >275° C. ¹NMR(DMSO-d₆) δ ppm: 2.88(s, 3H), 6.20(d,J=8Hz, 1H), 6.58(d, J=2Hz, 1H), 6.83(dd, J=2, 8Hz, 1H), 6.87(d, J=3Hz,1H), 6.96(d, J=3Hz, 1H), 9.13(s, 1H) 781

ESI (+) 259 (MH⁺) 244-251° C. ¹NMR(DMSO-d₆) δ ppm: 3.26(s, 3H), 3.59(s,3H), 4.99(s, 3H), 6.06(d, J=3Hz, 1H), 6.14(dd, J=3, 9Hz, 1H), 6.48(d,J=9Hz, 1H), 6.99(d, J=3Hz, 1H), 7.12(d, J=3Hz, 1H) Ex. Structuralformula NMR 782

¹NMR(CDCl₃) δ ppm: 3.43(s, 3H), 3.45(s, 3H), 5.03(s, 2H), 5.11(s, 2H),6.05(s, 1H), 6.33(d, J=8Hz, 1H), 6.60(d, J=8Hz, 1H), 6.79(br · s, 1H),7.05(d, J=3Hz, 1H), 7.13(d, J=3Hz, 1H) 783

¹NMR(CDCl₃) δ ppm: 3.38(s, 3H), 5.07(s, 2H), 6.36(s, 1H), 6.61(d, J=8Hz,1H), 6.89(d, J=8Hz, 1H), 7.08(d, J=3Hz, 1H), 7.14(d, J=3Hz, 1H)

Example 784 5,10-Dihydro-7-hydroxy-10H-pyrazino[2,3-b][1,4]quinoxalinehydrochloride

5,10-Dihydro-5-methoxymethyl-8-methoxymethoxy-10H-pyrazino[2,3-b][1,4]quinoxalinewas treated by the same method as the one of Example 8 to thereby givethe title compound.

¹H-NMR(DMSO-d₆) δ ppm 6.07(d, J=8 Hz, 1H), 6.11(s, 1H), 6.46(d, J=8 Hz,1H), 6.49(br.s, 1H), 6.56(br.s, 1H)

m.p.: >275° C.

MS: ESI(+)201(MH⁺)

Examples

The compounds obtained in Examples 767 and 779 were treated by the samemethod as the one of Example 8 to thereby give the following compounds.

Ex. Structural formula MS M.p. NMR 785

ESI (+) 319 (MH⁺) 253-255° C. ¹NMR(DMSO-d₆) δ ppm: 4.90(s, 2H), 6.15(d,J=8Hz, 1H), 6.36(d, J=8Hz, 1H), 6.39(t, J=8Hz, 1H), 6.49(t, J=8Hz, 1H),6.88(d, J=3Hz, 1H), 6.90(d, J=3Hz, 1H), 7.43(d, J=9Hz, 2H), 7.88(d,J=8Hz, 2H), 9.18(s, 1H) 786

¹NMR(DMSO-d₆) δ ppm: 2.96(s, 3H), 6.47(d, J=8Hz, 1H), 6.85(d, J=2Hz,1H), 6.91(d, J=3Hz, 1H), 6.98(d, J=3Hz, 1H), 7.15(dd, J=2, 8Hz, 1H),9.23(s, 1H)

Example 787 (5,10-Dihydro-10H-pyrazino[2,3-b][1,4]quinoxalin-5-yl)aceticacid

The title compound was obtained by treating tert-butyl(5,10-dihydro-10H-pyrazino[2,3-b][1,4]quinoxalin-5-yl)acetate by thesame method as the one of Example 9.

¹H-NMR(DMSO-d₆) δ ppm: 4.26(s, 2H), 6.33(dd, J=2, 8 Hz, 1H), 6.37(dd,J=2, 8 Hz, 1H), 6.51(dt, 2, 8 Hz, 1H), 6.54(dt, J=2, 8 Hz, 1H), 6.91(d,J=3 Hz, 1H), 6.93(d, J=3 Hz, 1H), 9.14(s, 1H)

m.p.: 210-212° C.

MS: ESI(+)243(MH⁺)

Example 7885,10-Dihydro-7-methoxy-5-methyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]quinoxaline

0.258 g of5,10-dihydro-5-methoxymethyl-8-methoxy-10H-pyrazino[2,3-b][1,4]quinoxalinein N,N-dimethylformamide (20 ml) was degassed at 0° C. in a nitrogenatmosphere. After adding 0.050 g of sodium hydride (60% or above), theresulting mixture was stirred for 30 minutes. Then a solution of 0.13 mlof methyl iodide in N,N-dimethylformamide (5 ml) was dropped thereintoat the same temperature and the resulting mixture was stirred at roomtemperature for 16 hours. The reaction mixture was distributed intoethyl acetate and water and the aqueous layer was extracted with ethylacetate. Then the organic layers were combined, washed successively withwater and a saturated aqueous solution of sodium chloride and dried overmagnesium sulfate. After distilling off the solvent under reducedpressure, the residue was purified by silica gel column chromatography(eluted with n-hexane/ethyl acetate) to thereby give 0.234 g of thetitle compound as a yellow solid.

¹H-NMR(CDCl₃) δ ppm: 3.13(s, 3H), 3.44(s, 3H), 3.75(s, 3H), 5.16(s, 2H),6.13(s, 1H), 6.21(d, J=8 Hz, 1H), 6.65(d, J=8 Hz, 1H), 7.14(s, 1H),7.18(s, 1H)

Examples

The compounds obtained in Examples 783 and 782 were treated by the samemethod as the one of Example 788 to thereby give the followingcompounds.

Ex. Structural formula NMR 789

¹NMR(CDCl₃) δ ppm: 3.13(s, 3H), 3.43(s, 3H), 3.47(s, 3H), 5.08(s, 2H),5.13(s, 2H), 6.23(d, J=2Hz, 1H), 6.40(dd, J=2, 8Hz, 1H), 6.63(d, J=8Hz,1H), 7.10(d, J=3Hz, 1H), 7.17(d, J=3Hz, 1H) 790

¹NMR(CDCl₃) δ ppm: 3.04(s, 3H), 3.38(s, 3H), 5.09(s, 2H), 6.49(s, 1H),6.62(d, J=8Hz, 1H), 6.93(d, J=8Hz, 1H), 7.10(s, 1H), 7.19(s, 1H)

Examples

The compounds obtained in Examples 782, 790 and 788 were treated by thesame method as the one of Example 8 to thereby give the followingcompounds.

Ex. Structural formula MS M.p. NMR 791

ESI (+) 215 (MH⁺) >275° C. ¹NMR(DMSO-d₆) δ ppm: 3.02(s, 3H), 6.25(br ·s, 2H), 6.59(br · s, 2H), 6.81(br · s, 1H) 792

FAB (+) 223 (M⁺) >275° C. ¹NMR(DMSO-d₆) δ ppm: 2.92(s, 3H), 6.34(d,J=8Hz, 1H), 6.69(s, 1H), 6.94(d, J=3Hz, 1H), 6.98(d, J=8Hz, 1H), 7.05(d,J=3Hz, 1H), 9.58(s, 1H) 793

ESI (+) 228 (M⁺) 195-197° C. ¹NMR(DMSO-d₆) δ ppm: 2.95(s, 3H), 3.61(s,3H), 6.07(br · s, 1H), 6.12(br · d, J=8Hz, 1H), 6.25(br · d, J=8Hz, 1H),684(br · s, 1H), 6.91(br · s, 1H), 8.92(br · s, 1H)

Examples

The following compounds were obtained by treating5,10-dihydro-5-methoxymethyl-10H-pyrazino[2,3-b][1,4]quinoxaline by thesame method as the one of Example 788 by using appropriate halides as asubstitute for methyl iodide.

Ex. Structural formula NMR 794

¹NMR(CDCl₃) δ ppm: 1.20(t, J=7Hz, 3H), 2.57(t, J=8Hz, 2H), 3.38(s, 3H),3.95(t, J=8Hz, 2H), 4.09(q, J=7Hz, 2H), 5.07(s, 2H), 6.45(dd, J=2, 8Hz,1H), 6.63- 6.70(m, 3H), 7.04(d, J=2Hz, 1H), 7.10(d, J=2Hz, 1H) 795

¹NMR(CDCl₃) δ ppm: 3.47(s, 3H), 3.72(s, 3H), 4.50(br · m, 2H), 5.09(s,2H), 6.02(br · d, J=16Hz, 1H), 6.28(br · d, J=8Hz, 1H), 6.67- 6.77(m,3H), 6.92(td, J=6, 16Hz, 1H), 7.14(s, 2H)

Example 796

Ethyl 3-(5,10-dihydro-10H-pyrazino[2,3-b][1,4]quinoxalin-5-yl)propanoate

The title compound was obtained by treating ethyl3-(5,10-dihydro-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]quinoxalin-5-yl)propanoateby the same method as the one of Example 8.

¹H-NMR(CDCl₃) δ ppm: 1.20(t, J=7 Hz, 3H), 2.55(t, J=7 Hz, 2H), 3.88(t,J=7 Hz, 2H), 4.09(q, J=7 Hz, 2H), 6.14(d, J=8 Hz, 1H), 6.38(d, J=8 Hz,1H), 6.42(t, J=8 Hz, 1H), 6.56(t, J=8 Hz, 1H), 6.84(d, J=3 Hz, 1H),6.98(d, J=3 Hz, 1H)

MS: ESI(+)285(MH⁺)

m.p.:

Example 7975,10-Dihydro-5-[4-(N,N-dimethylamino)-2-buten-1-yl)]-10H-pyrazino[2,3-b][1,4]quinoxaline

0.0060 g of the title compound was obtained by treating 0.170 g of(E)-2-[N-(4-dimethylamino-2-buten-1-yl)-N-(2-nitrophenyl)amino]-3-chloropyrazineby the same method as the one of Example 763.

¹H-NMR(DMSO-d₆) δ ppm: 2.62(s, 6H), 3.65(m, 2H), 4.26(m, 2H), 5.72(td,J=8, 16 Hz, 1H), 5.93(td, J=5, 16 Hz, 1H), 6.35-6.39(m, 2H),6.51-6.54(m, 2H), 6.87(d, J=3 Hz, 1H), 6.91(d, J=3 Hz, 1H), 9.20(s, 1H)

MS: ESI(+)282(MH⁺)

Example 798 5,10-Dihydro-5-propyl-10H-pyrazino[2,3-b][1,4]quinoxaline

0.188 g of the title compound was obtained as yellow crystals bytreating 0.224 g of5,10-dihydro-5-allyl-10H-pyrazino[2,3-b][1,4]quinoxaline by the samemethod as the one of Example 20.

¹H-NMR(CDCl₃) δ ppm: 0.98(t, J=7 Hz, 3H), 1.55-1.68(m, 2H), 3.56(t, J=8Hz, 2H), 6.18(d, J=8 Hz, 1H), 6.35(d, J=8 Hz, 1H), 6.55(t, J=8 Hz, 1H),6.62(t, J=8 Hz, 1H), 6.86(d, J=3 Hz, 1H), 7.03(d, J=3 Hz, 1H)

m.p.: 190-192° C.

MS: ESI(+)227(MH⁺)

Example 799 Methyl4-(5,10-dihydro-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]quinoxalin-5-yl)butanoate

The title compound was obtained by treating methyl4-(5,10-dihydro-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]quinoxalin-5-yl)-2-butenoateby the same method as the one of Example 20.

¹H-NMR(CDCl₃) δ ppm: 1.87(quint, J=7 Hz, 2H), 2.38(t, J=7 Hz, 2H),3.38(s, 3H), 3.63(s, 3H), 3.67(t, J=7 Hz, 2H), 5.06(s, 2H), 6.55(d, J=8Hz, 1H), 6.61-6.65(m, 2H), 6.69(ddd, J=2, 6, 8 Hz, 1H), 7.00(d, J=3 Hz,1H), 7.06(d, J=3 Hz, 1H)

Example 800 Methyl4-(5,10-dihydro-10H-pyrazino[2,3-b][1,4]quinoxalin-5-yl)butanoate

The title compound was obtained by treating methyl4-(5,10-dihydro-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]quinoxalin-5-yl)-2-butenoateby the same method as the one of Example 8.

¹H-NMR(CDCl₃) δ ppm: 1.92.(quint, J=7 Hz, 2H), 2.44(t, J=7 Hz, 2H),3.68(t, J=7 Hz, 2H), 3.70(s, 3H), 6.18(d, J=8 Hz, 1H), 6.53-6.59(m, 2H),7.05(t, J=8 Hz, 1H), 6.87(d, J=3 Hz, 1H), 7.00(d, J=3 Hz, 1H)

m.p.: 189-190° C.

MS: ESI(+)285(MH⁺)

Example 8015,10-Dihydro-5-methoxymethyl-10-methyl-10H-pyrazino[2,3-b][1,4]quinoxaline-7-carbonitrile

2.43 g of the title compound was obtained as yellow crystals by reacting3.14 g of5,10-dihydro-10-methyl-10H-pyrazino[2,3-b][1,4]quinoxaline-7-carbonitrilewith chloromethyl methyl ether by the same method as the one of Example788.

¹H-NMR(CDCl₃) δ ppm: 3.16(s, 3H), 3.45(s, 3H), 5.11(s, 2H), 6.42(d, J=8Hz, 1H), 6.86(d, J=2 Hz, 1H), 7.05(dd, J=2, 8 Hz, 1H), 7.21(d, J=3 Hz,1H), 7.26(d, J=3 Hz, 1H)

Example 8025,10-Dihydro-5-methoxymethyl-10-methyl-10H-pyrazino[2,3-b][1,4]quinoxaline-7-carboxamide

0.267 g of5,10-dihydro-5-methoxymethyl-10-methyl-10H-pyrazino[2,3-b][1,4]quinoxaline-7-carbonitrilewas dissolved at 0° C. in 20 ml of ethanol and 20 ml of dimethylsulfoxide. After adding 0.36 ml of a 30% aqueous solution of hydrogenperoxide and 0.36 ml of 6 N sodium hydroxide, the resulting mixture wasstirred at room temperature for 16 hours. Then the reaction mixture waspoured into water. The precipitate was taken up by filtration. andwashed with water to thereby give 0.271 g of the title compound as ayellow powder.

¹H-NMR(CDCl₃) δ ppm: 3.07(s, 3H), 3.31(s, 3H), 5.12(s, 2H), 6.61(d, J=8Hz, 1H), 7.12(d, J=1 Hz, 1H), 7.15(d, J=3 Hz, 1H), 7.16(br.s, 1H),7.22(d, J=3 Hz, 1H), 7.29(dd, J=1, 8 Hz, 1H), 7.77(br.s, 1H)

Example 8035,10-Dihydro-10-methyl-10H-pyrazino[2,3-b][1,4]quinoxaline-7-carboxamide

The title compound was obtained by treating5,10-dihydro-5-methoxymethyl-10-methyl-10H-pyrazino[2,3-b][1,4]quinoxaline-7-carboxamideby the same method as the one of Example 8.

¹H-NMR(DMSO-d₆) δ ppm: 2.95(s, 3H), 6.43(d, J=8 Hz, 1H), 6.81(s, 1H),6.89(d, J=3 Hz, 1H), 6.97(d, J=3 Hz, 1H), 7.06(br.s, 1H), 7.09(d, J=8Hz, 1H), 7.65(br.s, 1H), 9.18(s, 1H)

MS: ESI(+)263.9(MNa⁺)

Example 8045,10-Dihydro-5-methoxymethyl-10-methyl-10H-pyrazino[2,3-b][1,4]quinoxaline-7-carbaldehyde

A solution of 1.068 g of5,10-dihydro-5-methoxymethyl-10-methyl-10H-pyrazino[2,3-b][1,4]quinoxaline-7-carbonitrilein toluene (100 ml) was degassed in a nitrogen atmosphere and cooled to−78° C. After dropping 9.6 ml of a 1.0 M solution of diisobutylaluminumhydride in toluene thereinto, the resulting mixture was heated to roomtemperature over 15 hours. Then the reaction mixture was cooled to 0° C.and the excessive reagent was decomposed with methanol. The reactionmixture was distributed into ethyl acetate and water. After filteringoff the insoluble matters, the aqueous layer was extracted with ethylacetate. The organic layers were combined, washed successively withwater and a saturated aqueous solution of sodium chloride and dried overanhydrous magnesium sulfate. After distilling off the solvent underreduced pressure, the residue was purified by silica gel columnchromatography (eluted with n-hexane/ethyl acetate) to thereby give0.519 g of the title compound as a yellow solid.

¹H-NMR(CDCl₃) δ ppm:

3.13(s, 3H), 3.33(s, 3H), 5.13(s, 2H), 6.75(d, J=8 Hz, 1H), 7.01(d, J=2Hz, 1H), 7.24(d, J=3 Hz, 1H), 7.28(d, J=3 Hz, 1H), 7.35(dd, J=2, 8 Hz,1H), 9.67(s, 1H)

Example 805Ethyl(E)-3-(5,10-dihydro-5-methoxymethyl-10-methyl-10H-pyrazino[2,3-b][1,4]quinoxalin-7-yl)propenoate

The title compound was obtained by treating5,10-dihydro-10-methyl-5-methoxymethyl-10H-pyrazino[2,3-b][1,4]quinoxaline-7-carbaldehydeby the same method as the one of Production Example 25.

¹H-NMR(CDCl₃) δ ppm: 1.26(t, J=7 Hz, 3H), 3.09(s, 3H), 3.40(s, 3H),4.18(q, J=7 Hz, 2H), 5.11(s, 2H), 6.18(d, J=16 Hz, 1H), 6.38(d, J=8 Hz,1H), 6.91(d, J=2 Hz, 1H), 6.86(dd, J=2, 8 Hz, 1H), 7.09(d, J=3 Hz1H),7.16(d, J=3 Hz, 1H), 7.43(d, J=16 Hz, 1H)

Examples

The following compounds were obtained by hydrolyzing the compoundsobtained in Examples 805 and 799 by the same method as the one ofExample 18.

Ex. Structural formula NMR 806

¹NMR(DMSO-d₆) δ ppm: 3.07(s, 3H), 3.42(s, 3H), 5.17(s, 2H), 6.26(d,J=16Hz, 1H), 6.61(d, J=8Hz, 1H), 6.88(d, J=1Hz, 1H), 7.07(dd, J=1, 8Hz,1H), 7.16(d, J=3Hz, 1H), 7.24(d, J=3Hz, 1H), 7.38(d, J=16Hz, 1H),12.20(br · s, 1H) 807

¹NMR(CDCl₃) δ ppm: 1.89(quint, J=7Hz, 2H), 2.42(t, J=7Hz, 2H), 3.38(s,3H), 3.69(br · t, J=7Hz, 2H), 5.06(s, 2H), 6.52(d, J=8Hz, 1H),6.60-6.71(m, 3H), 7.01-7.04(m, 2H)

Examples

The following compounds were obtained by treating the compounds obtainedin Examples 806 and 807 by the same method as the one of Example 8.

Ex. Structural formula MS M.p. NMR 808

ESI (+) 269 (MH⁺) 275° C. ¹NMR(DMSO-d₆) δ ppm: 2.97(s, 3H), 6.05(d,J=16Hz, 1H), 6.46(d, J=8Hz, 1H), 6.55(d, J=1Hz, 1H), 6.87(dd, J=1, 8Hz,1H), 6.90(d, J=3Hz, 1H), 6.99(d, J=3Hz, 1H), 7.27(d, J=16Hz, 1H),9.13(s, 1H) 809

ESI (+) 271 (MH⁺) 273-274° C. ¹NMR(DMSO-d₆) δ ppm: 1.66(quint, J=7Hz,2H), 2.28(t, J=7Hz, 2H), 3.53(t, J=7Hz, 2H), 6.31(d, J=8Hz, 1H), 6.49-6.55(m, 3H), 6.81(d, J=3Hz, 1H), 6.90(d, J=3Hz, 1H), 9.03(s, 1H)

Example 8105,10-Dihydro-5-methoxymethyl-10-methyl-7-(oxazol-5-yl)-10H-pyrazino[2,3-b][1,4]quinoxaline

To 15 ml of methanol were added 0.166 g of5,10-dihydro-10-methyl-5-methoxymethyl-10H-pyrazino[2,3-b][1,4]quinoxaline-7-carbaldehyde,0.120 g of p-toluenesulfonylmethyl isocyanide and 0.081 g of potassiumcarbonate and the resulting mixture was heated under reflux for 90minutes. After distilling off the solvent under reduced pressure, theresidue was dissolved in ethyl acetate, washed successively with a 1 Naqueous solution of sodium hydroxide, water and a saturated aqueoussolution of sodium chloride and dried over anhydrous magnesium sulfate.After distilling off the solvent under reduced pressure, the residue waspurified by silica gel column chromatography (eluted with n-hexane/ethylacetate) to thereby give 0.134 g of the title compound as a yellowsolid.

¹H-NMR(CDCl₃) δ ppm: 3.16(s, 3H), 3.47(s, 3H), 5.22(s, 2H), 6.49(d, J=8Hz, 1H), 6.97(d, J=2 Hz, 1H), 7.05(dd, J=2, 8 Hz, 1H), 7.15(d, J=3 Hz,1H), 7.21(s, 1H), 7.22(d, J=3 Hz, 1H), 7.86(s, 1H)

Example 8115,10-Dihydro-10-methyl-5-methoxymethyl-10H-pyrazino[2,3-b][1,4]quinoxaline-7-methanol

The title compound was obtained by treating5,10-dihydro-10-methyl-5-methoxymethyl-10H-pyrazino[2,3-b][1,4]quinoxaline-7-carbaldehydeby the same method as the one of Example 2.

¹H-NMR(CDCl₃) δ ppm: 3.12(s, 3H), 3.35(s, 3H), 3.46(s, 3H), 4.27(s, 2H),5.17(s, 2H), 6.45(d, J=8 Hz, 1H), 6.70(s, 1H), 6.74(d, J=8 Hz, 1H),7.10(d, J=3 Hz, 1H), 7.18(d, J=3 Hz, 1H)

Example 8125,10-Dihydro-10-methyl-5,7-dimethoxymethyl-7-10H-pyrazino[2,3-b][1,4]quinoxaline

The title compound was obtained by treating5,10-dihydro-10-methyl-5-methoxymethyl-10H-pyrazino[2,3-b][1,4]quinoxaline-7-methanolby the same method as the one of Example 788.

¹H-NMR(CDCl₃) δ ppm: 3.12(s, 3H), 3.45(s, 3H), 4.50(d, J=6 Hz, 2H),5.17(s, 2H), 6.44(d, J=8 Hz, 1H), 6.72(d, J=2 Hz, 1H), 6.76(dd, J=2, 8Hz, 1H), 7.11(d, J=3 Hz, 1H), 7.19(d, J=3 Hz, 1H)

Examples

The following compounds were obtained by treating the compounds obtainedin Examples 804, 805, 810, 811 and 812 by the same method as the one ofExample 8.

Ex. Structural formula MS M.p. NMR 813

ESI (+) 227 (MH⁺) 215-219° C. ¹NMR(DMSO-d₆) δ ppm: 3.00(s, 3H), 6.58(d,J=8Hz, 6.70(s, 1H), 6.97(d, J=3Hz, 1H), 7.02(d, J=3Hz, 1H), 7.15(d,J=8Hz, 1H), 9.36(s, 1H), 9.55(s, 1H) 814

ESI (+) 297 (MH⁺) 190-191° C. ¹NMR(CDCl₃) δ ppm: 1.33(t, J=7Hz, 3H),3.20(s, 3H), 4.24(q, J=7Hz, 2H), 6.31(d, J=16Hz, 1H), 6.45(d, J=3Hz,1H), 6.60(d, J=8Hz, 1H), 6.85(d, J=2Hz, 1H), 6.97(d, J=3Hz, 1H),7.04(dd, J=2, 8Hz, 1H), 7.45(d, J=16Hz, 1H) 815

ESI (+) 266 (MH⁺) 268-269° C. ¹NMR(DMSO-d₆) δ ppm: 2.98(s, 3H), 6.51(d,J=8Hz, 1H), 6.64(d, J=2Hz, 1H), 6.90(d, J=4Hz, 1H), 6.93(dd, J=2, 8Hz,1H), 6.98(d, J=4Hz, 1H), 7.37(s, 1H), 8.33(s, 1H), 9.23(s, 1H) 816

ESI (+) 229 (MH⁺) 215-218° C. ¹NMR(DMSO-d₆) δ ppm: 2.93(s, 3H), 4.18(d,J=6Hz, 2H), 4.97(t, J=6Hz, 1H), 6.33(s, 1H), 6.37(d, J=8Hz, 1H), 6.47(d,J=8Hz, 1H), 6.82(d, J=3Hz, 1H), 6.92(d, J=3Hz, 1H), 9.07(s, 1H) 817

ESI (+) 243 (MH⁺) 169-172° C. ¹NMR(DMSO-d₆) δ ppm: 2.94(s, 3H), 3.19(s,3H), 4.08(s, 2H), 6.30(s, 1H), 6.36(d, J=8Hz, 1H), 6.48(d, J=8Hz, 1H),6.84(d, J=4Hz, 1H), 6.94(d, J=4Hz, 1H), 9.08(s, 1H)

Example 818(5,10-Dihydro-5-methoxymethyl-10-methyl-10H-pyrazino[2,3-b]-[1,4]quinoxalin-7-yl)-(pyridin-3-yl)methanol

Into a solution of 0.22 g of 3-bromopyridine in dry diethyl ether (10ml) was dropped 0.7 ml of a 1.6 M solution of n-butyllithium in hexaneat −78° C. in a nitrogen atmosphere. After stirring for 1 hour, asolution of 0.126 g of5,10-dihydro-5-methoxymethyl-10-methyl-10H-pyrazino[2,3-b][1,4]quinoxaline-7-carbaldehydein tetrahydrofuran (3 ml) was dropped into the reaction mixture and thenthe bulk temperature was elevated to −20° C. After adding a saturatedaqueous solution of sodium dihydrogenphosphate, the resulting mixturewas extracted with ethyl acetate. The organic layers were combined,washed successively with water and a saturated aqueous solution ofsodium chloride and dried over anhydrous magnesium sulfate. Afterdistilling off the solvent under reduced pressure, the residue waspurified by silica gel column chromatography (eluted with n-hexane/ethylacetate) to thereby give 0.100 g of the title compound as a yellowsolid.

¹H-NMR(CDCl₃) δ ppm: 3.10(s, 3H), 3.41(s, 3H), 5.12(s, 2H), 5.70(s, 1H),6.42(d, J=8 Hz, b 1l H), 6.71(dd, J=2, 8 Hz, 1H), 6.72(d, J=2 Hz, 1H),7.11(d, J=3 Hz, 1H), 7.19(d, J=3 Hz, 1H) 7.27(dd, J=5, 8 Hz, 1H)7.71(td, J=2, 8 Hz, 1H), 8.51(dd, J=2, 5 Hz, 1H), 8.62(d, J=2 Hz, 1H)

Examples

The following compounds were obtained by treating5,10-dihydro-5-methoxymethyl-10-methyl-10H-pyrazino[2,3-b][1,4]quinoxaline-7-carbaldehydewith appropriate alkyl-metals or arylmetals by the same method as theone of Example 818.

Ex. Structural formula NMR 819

¹H-NMR(CDCl₃) δ ppm: 3.11(s, 3H), 3.42(s, 3H), 3.43(br.s, 1H), 5.12(s,2H), 5.88(s, 1H), 6.43(d, J=8Hz, 1H), 6.80(d, J=2Hz, 1H), 6.83(dd, J=2,8Hz, 1H), 7.11(d, J=3Hz, 1H), 7.19(d, J=3Hz, 1H), 7.31(d, J=3Hz, 1H),7.74(d, J=3Hz, 1H) 820

¹H-NMR(CDCl₃) δ ppm: 2.37(s, 1H), 3.12(s, 3H), 3.41(s, 3H), 5.11(d,J=11Hz, 1H), 5.15(d, J=11Hz, 1H), 5.89(s, 1H), 6.44(d, J=8Hz, 1H),6.79(d, J=2Hz, 1H), 6.83(dd, J=2, 8Hz, 1H), 6.92-6.96(m, 2H), 7.11(d,J=3Hz, 1H), 7.19(d, J=3Hz, 1H), 7.25-7.28(m, 1H) 821

¹H-NMR(CDCl₃) δ ppm: 3.11(s, 3H), 3.40(s, 3H), 5.12(s, 2H), 5.15(d,J=4Hz, 1H), 5.59(d, J=4Hz, 1H), 6.42(d, J=8Hz, 1H), 6.73(d, J=2Hz, 1H),6.75(dd, J=2, 8Hz, 1H), 7.09(d, J=3Hz, 1H), 7.16-7.24(m, 3H), 7.65(dt,J=1, 8Hz, 1H), 8.56(ddd, J=1, 2, 6Hz, 1H) 822

¹H-NMR(CDCl₃) δ ppm: 2.21(s, 1H), 3.09(s, 3H), 3.39(s, 3H), 5.16(d,J=9Hz, 1H), 5.22(d, J=9Hz, 1H), 5.78(s, 1H), 6.41(d, J=8Hz, 1H), 6.73(d,J=8Hz, 1H), 6.74(s, 1H), 7.09(d, J=3Hz, 1H), 7.18(d, J=3Hz, 1H),7.25-7.39(m, 5H) 823

¹H-NMR(CDCl₃) δ ppm: 2.36(br.s, 1H), 3.13(s, 3H), 3.45(s, 3H), 5.18(s,2H), 5.51(d, J=5Hz, 1H), 6.47(d, J=8Hz, 1H), 6.98(d, J=2Hz, 1H),7.00(dd, J=2, 8Hz, 1H), 7.12(d, J=3Hz, 1H), 7.20(d, J=3Hz, 1H),7.29-7.34(m, 3H), 7.45-7.48(m, 2H) 824

¹H-NMR(CDCl₃) δ ppm: 2.79(s, 6H), 3.07(s, 3H), 3.38(s, 3H), 5.01(d,J=11Hz, 1H), 5.10(d, J=11Hz, 1H), 6.04(s, 1H), 6.39(d, J=8Hz, 1H),6.68(d, J=2Hz, 1H), 6.75(dd, J=2, 8Hz, 1H), 7.06(d, J=2Hz, 1H), 7.09(d,J=3Hz, 1H), 7.16(d, J=3Hz, 1H), 7.23(d, J=2Hz, 1H)

Example 825(5,10-Dihydro-10-methyl-5-methoxymethyl-10H-pyrazino[2,3-b][1,4]quinoxalin-7-yl)-(1,2,4-triazol-3-yl)methanol

To a solution of 0.404 g of 1-diethoxymethyl-1,2,4-triazole in drytetrahydrofuran (10 ml) was added at 0° C. in a nitrogen atmosphere 1.5ml of a 1.5 M solution of n-butyllithium in hexane. After stirring for 1hour, the resulting mixture was cooled to −78° C. Then a solution of0.270 g of5,10-dihydro-5-methoxymethyl-10-methyl-10H-pyrazino[2,3-b][1,4]quinoxaline-7-carbaldehydein dry tetrahydrofuran (10 ml) was dropped thereinto and the bulktemperature was elevated to room temperature. After stirring for 16hours, a saturated aqueous solution of sodium dihydrogenphosphate wasadded and the resulting mixture was extracted with ethyl acetate. Theorganic layers were combined, washed successively with water and asaturated aqueous solution of sodium chloride and dried over anhydrousmagnesium sulfate. After distilling off the solvent under reducedpressure, the residue was purified by silica gel column chromatography(eluted with n-hexane/ethyl acetate) to thereby give 0.170 g of thetitle compound as a yellow solid.

¹H-NMR(CDCl₃) δ ppm: 3.02(s, 3H), 3.29(s, 3H), 5.04(s, 2H), 5.53 and5.64(s, total 1H), 5.64(s, 1H), 6.55(d, J=8 Hz, 1H), 6.73-6.89(m, 2H),7.10(d, J=3 Hz, 1H), 7.18(d, J=3 Hz, 1H), 7.79 and 8.43(s, total 1H),13.90(s, 1H)

Examples

The following compounds were obtained by the same method as the one ofExample 8.

Ex. Structural formula MS M. p. NMR 826

ESI (+) 306 (MH⁺) 131-134° C. ¹H-NMR(DMSO-d₆) δ ppm: 2.91(s, 3H),5.46(d, J=5Hz, 1H), 5.88(d, J=5Hz, 1H), 6.36(d, J=2Hz, 1H), 6.36(d,J=8Hz, 1H), 6.55(dd, J=2, 8Hz, 1H), 6.83(d, J=4Hz, 1H), 6.92(d, J=4Hz,1H), 7.31(dd, J=6, 8Hz, 1H), 7.63(td, J=2, 8Hz, 1H), # 8.40(dd, J=2,6Hz, 1H), 8.50(d, J=2Hz, 1H), 9.01(s, 1H) 827

ESI (+) 334 (MNa⁺) 203-204° C. ¹H-NMR(DMSO-d₆) δ ppm: 2.92(s, 3H),5.62(d, J=5Hz, 1H), 6.38(d, J=8Hz, 1H), 6.43(s, 1H), 6.57(d, J=5Hz, 1H),6.60(d, J=8Hz, 1H), 6.83(d, J=3Hz, 1H), 6.93(d, J=3Hz, 1H), 7.59(d,J=4Hz, 1H), 7.66(d, J=4Hz, 1H), 9.05(s, 1H) 828

ESI (+) 311 (MH⁺) >275° C. ¹H-NMR(DMSO-d₆) δ ppm: 2.93(s, 3H), 5.62(d,J=5Hz, 1H), 6.02(d, J=5Hz, 1H), 6.37(d, J=8Hz, 1H), 6.43(s, 1H), 6.56(d,J=8Hz, 1H), 6.82(d, J=4Hz, 1H), 6.83(d, J=6Hz, 1H), 6.90(d, J=6Hz, 1H),6.93(d, J=4Hz, 1H), # 7.36(d, J=6Hz, 1H), 9.05(s, 1H) 829

ESI (+) 328 (MH⁺) 171-173° C. ¹H-NMR(DMSO-d₆) δ ppm: 2.90(s, 3H),5.39(d, J=5Hz, 1H), 5.89(d, J=5Hz, 1H), 6.35(d, J=8Hz, 1H), 6.40(d,J=2Hz, 1H), 6.56(dd, J=2, 8Hz, 1H), 6.81(d, J=4Hz, 1H), 6.92(d, J=4Hz,1H), 7.21(dd, J=5, 8Hz, 1H), 7.45(d, J=8Hz, 1H), # 7.75(t, J=8Hz, 1H),8.42(d, J=5Hz, 1H), 9.00(s, 1H) 830

ESI (+) 305 (MH⁺) 127-132° C. ¹H-NMR(DMSO-d₆) δ ppm: 2.90(s, 3H),5.38(d, J=5Hz, 1H), 5.69(d, J=5Hz, 1H), 6.35(d, J=8Hz, 1H), 6.37(s, 1H),6.53(d, J=8Hz, 1H), 6.82(d, J=4Hz, 1H), 6.92(d, J=4Hz, 1H), 7.15-7.21(m,2H), 7.23- 7.28(m, 3H), 9.00(s, 1H) 831

ESI (+) 329 (MH⁺) 204-208° C. ¹H-NMR(CDCl₃) δ ppm: 3.11(s, 3H), 5.29(s,1H), 5.30(d, J=6Hz, 1H), 5.95(d, J=6Hz, 1H), 6.42(d, J=8Hz, 1H), 6.58(d,J=2Hz, 1H), 6.69(dd, J=2, 8Hz, 1H), 6.85(dd, J=1, 3Hz, 1H), 6.95(dd,J=1, 3Hz, 1H), 7.37(m, 3H), 7.42(m, 2H) 832

ESI (+) 424 (MNa⁺) 185-190° C. ¹H-NMR(DMSO-d₆) δ ppm: 2.84(s, 6H),2.93(s, 3H), 5, 83(s, 1H), 5.89(br.s, 1H), 6.37(d, J=8Hz, 1H), 6.46(d,J=2Hz, 1H), 6.52(dd, J=2, 8Hz, 1H), 6.83(d, J=4Hz, 1H), 6.94(d, J=4Hz,1H), 7.00(d, J=2Hz, 1H), 7.50(d, # J=2Hz, 1H), 9.06(s, 1H) 833

FAB (+) 296 (MH⁺) >275° C. ¹H-NMR(DMSO-d₆) δ ppm: 2.92(s, 3H), 5.54(s,1H), 6.37(m, 2H), 6.54(d, J=8Hz, 1H), 6.83(s, 1H), 6.93(s, 1H), 7.79(s,1H), 9.09(br.s, 1H), 13.86(br.s, 1H)

Example 834(5,10-Dihydro-5-methyl-10H-pyrazino[2,3-b][1,4]quinoxalin-8-yl)-(imidazol-2-yl)methanol

0.084 g ofN,N-dimethyl-[2-(5,10-dihydro-5-methyl-10H-pyrazino[2,3-b][1,4]quinoxalin-8-yl)hydroxymethyllimidazole-1-sulfonamide was dissolved in 4.5 ml of 35%hydrochloric acid in a nitrogen atmosphere and heated to 50° C. for 30hours. Then the reaction mixture was neutralized with a saturatedaqueous solution of sodium hydrogencarbonate and the solid thusprecipitated was taken up by filtration. This solid was dissolved in 6 Nhydrochloric acid. After filtering off the insoluble, matters, thesolution was neutralized again with a saturated aqueous solution ofsodium hydrogencarbonate. The crystals thus precipitated were taken upby filtration to thereby give 0.060 g of the title compound as ayellowish green solid.

¹H-NMR(DMSO-d₆) δ ppm: 2.92(s, 3H), 5.46(s, 1H), 6.10(br.s, 1H), 6.37(d,J=8 Hz, 1H), 6.38(s, 1H), 6.55(d, J=8 Hz, 1H), 6.83(d, J=3 Hz, 1H),6.94(d, J=3 Hz, 1H), 6.96(br.s, 2H), 9.08(br.s, 1H)

MS: ESI(+)295(MH⁺)

Example 835(5,10-Dihydro-5-methoxymethyl-10-methyl-10H-pyrazino[2,3-b][1,4]quinoxalin-7-yl)(pyridin-2-yl)ketone

The title compound was obtained by oxidizing(5,10-dihydro-5-methoxymethyl-10-methyl-10H-pyrazino2,3-b][1,4]quinoxalin-7-yl)-(pyridin-2-yl)methanol with manganesedioxide by the same method as the one of Example 625.

¹H-NMR(CDCl₃) δ ppm: 3.19(s, 3H), 3.45(s, 3H), 5.20(s, 2H), 6.50(d, J=8Hz, 1H), 7.20(d, J=3 Hz, 1H), 7.24(d, J=3 Hz, 1H), 7.46(ddd, J=1, 5, 8Hz, 1H), 7.49(d, J=2 Hz, 1H), 7.61(dd, J=2, 8 Hz, 1H), 7.86(dt, J=2, 8Hz, 1H), 7.77(td, J=1, 8 Hz, 1H), 8.69(ddd, J=1, 2, 5 Hz, 1H)

Example 8361-(5,10-Dihydro-5-methoxymethyl-10-methyl-10H-pyrazino[2,3-b][1,4]quinoxalin-7-yl)-1-(pyridin-2-yl)ethanol

The title compound was obtained by treating(5,10-dihydro-5-methoxymethyl-10-methyl-10H-pyrazino[2,3-b][1,4]quinoxalin-7-yl)(pyridin-2-yl)ketone with methyllithium by the same method as the one of Example 818.

¹H-NMR(CDCl₃) δ ppm: 1.85(s, 3H), 3.08(s, 3H), 3.38(s, 3H), 5.09(s, 2H),5.75(s, 1H), 6.49(d, J=8 Hz, 1H), 6.82(d, J=2 Hz, 1H), 6.86(dd, J=2, 8Hz, 1H), 7.09(d, J=3 Hz, 1H), 7.16(d, J=3 Hz, 1H), 7.17(dd, J=5, 8 Hz,1H), 7.31(d, J=8 Hz, 1H), 7.66(dt, J=1, 8 Hz, 1H), 8.52(dd, J=1, 5 Hz,1H)

Example 837[(5,10-Dihydro-5-methoxymethyl-10-methyl-10H-pyrazino[2,3-b][1,4]quinoxalin-7-yl)-(pyridin-2-yl)methyl]acetate

0.192 g of the title compound was obtained as a yellow solid by treating0.202 g of(5,10-dihydro-5-methoxymethyl-10-methyl-10H-pyrazino[2,3-b][1,4]quinoxalin-7-yl)-(pyridin-2-yl)methanolwith 0.5 ml of acetic anhydride in the presence of 5 ml of pyridine bythe same method as the one of Production Example 165.

¹H-NMR(CDCl₃) δ ppm: 2.19(s, 3H), 3.08(s, 3H), 3.40(s, 3H), 5.09(s, 2H),6.40(d, J=8 Hz, 1H), 6.68(s, 1H), 6.75(d, J=2 Hz, 1H), 6.80(dd, J=2, 8Hz, 1H), 7.09(d, J=3 Hz, 1H), 7.17(d, J=3 Hz, 1H), 7.19(ddd, J=1, 5, 8Hz, 1H), 7.40(br.t, J=8 Hz, 1H), 7.67(dt, J=2, 8 Hz, 1H), 8.58(ddd, J=1,2, 5 Hz, 1H)

Example 8385,10-Dihydro-5-methoxymethyl-10-methyl-7-[(piperidin-2-yl)methyl]-10H-pyrazino[2,3-b][1,4]quinoxaline

0.019 g of the title compound was obtained as a yellow solid byhydrogenating 0.096 g of[(5,10-dihydro-5-methoxymethyl-10-methyl-10H-pyrazino[2,3-b][1,4]quinoxalin-7-yl)-(pyridin-2-yl)methyl)acetate in a solvent [ethanol (10 ml)/acetic acid (0.2 ml)] in thepresence of 0.12 g of a 10% palladium-carbon powder (moisture content:50%) by the same method as the one of Example 20.

¹H-NMR(CDCl₃) δ ppm: 1.30-1.41(m, 1H), 1.48-1.60(m, 1H), 1.74-1.87(m,4H), 2.65(dd, J=9, 13 Hz, 1H), 2.79(dd, J=5, 13 Hz, 1H), 2.95-3.07(m,3H), 3.07(s, 3H), 3.36-3.42(m, 1H), 3.44(s, 3H), 5.12(s, 2H), 6.36(d,J=8 Hz, 1H), 6.53(d, J=2 Hz, 1H), 6.60(dd, J=2, 8 Hz, 1H), 7.08(d, J=3Hz, 1H), 7.17(d, J=3 Hz, 1H)

Example 8395,10-Dihydro-5-methoxymethyl-10-methyl-7-[(pyridin-2-yl)methyl]-10H-pyrazino[2,3-b][1,4]quinoxaline

0.160 g of the title compound was obtained as a yellow solid byhydrogenating 0.194 g of[(5,10-dihydro-5-methoxymethyl-10-methyl-10H-pyrazino[2,3-b][1,4]quinoxalin-7-yl)-(pyridin-2-yl)methyl]acetate in a mixture (15 ml) of tetrahydrofuran with ethanol (1:1) inthe presence of 0.12 g of a 10% palladium-carbon powder (moisturecontent: 50%) by the same method as the one of Example 20.

¹H-NMR(CDCl₃) δ ppm: 3.03(s, 3H), 3.46(s, 3H), 4.05(s, 2H), 5.10(s, 2H),6.37(d, J=8 Hz, 1H), 6.61(m, 2H), 7.01(d, J=3 Hz, 1H), 7.09(d, J=3 Hz,1H), 7.21(m, 1H), 7.62(dt, J=2, 8 Hz, 1H), 7.70(br.t, J=8 Hz, 1H),8.51(m, 1H)

Examples

The following compounds were obtained by treating the compounds obtainedin Examples 835, 836, 838 and 839 by the same method as the one ofExample 8.

Ex. Structural formula MS M. p. NMR 840

ESI (+) 326 (MNa⁺) 261-262° C. ¹H-NMR(DMSO-d₆) δ ppm: 3.01(s, 3H),6.52(d, J=8Hz, 1H), 6.95(d, J=4Hz, 1H), 6.98(d, J=2Hz, 1H), 7.02(d,J=4Hz, 1H), 7.28(dd, J=2, 8Hz, 1H), 7.60(dd, J=5, 8Hz, 1H), 7.82(d,J=8Hz, 1H), 8.00(dt, J=1, 8Hz, 1H), 8.57(dd, # J=1, 5Hz, 1H), 9.28(s,1H) 841

ESI (+) 342 (MH⁺) 185-187° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.71(s, 3H),2.89(s, 3H), 5.74(s, 1H), 6.32(d, J=8Hz, 1H), 6.53(d, J=2Hz, 1H),6.62(dd, J=2, 8Hz, 1H), 6.80(d, J=4Hz, 1H), 6.90(d, J=4Hz, 1H), 7.18(dd,J=6, 8Hz, 1H), 7.56(d, J=8Hz, 1H), # 7.71(dt, J=2, 8Hz, 1H), 8.44(dd,J=2, 6Hz, 1H), 8.95(s, 1H) 842

¹H-NMR(CDCl₃) δ ppm: 0.84-0.88(m, 1H), 1.04- 1.12(m, 1H), 1.16- 1.28(m,3H), 2.19- 2.30(m, 1H), 2.36- 2.50(m, 3H), 2.92- 3.05(m, 2H), 3.00(s,3H), 5.95(br.s, 1H), 6.01(d, J=2Hz, 1H), 6.25(d, J=8Hz, 1H), 6.43(dd,J=2, 8Hz, 1H), 6.84(d, J=3Hz, 1H), 7.01(d, J=3Hz, 1H) 843

ESI (+) 290 (MH⁺) ¹H-NMR(CDCl₃) δ ppm: 3.05(s, 3H), 3.88(s, 2H), 6.13(d,J=2Hz, 1H), 6.34(d, J=8Hz, 1H), 6.55(dd, J=2, 8Hz, 1H), 6.88(d, J=4Hz,1H), 7.06(d, J=4Hz, 1H), 7.12(d, J=8Hz, 1H), 7.12(dd, J=6, 8Hz, 1H),7.59(dt, J=2, 8Hz, 1H), # 8.54(dd, J=2, 6Hz, 1H)

Example 844Methyl(5,10-dihydro-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]quinoxalin-5-yl)acetate

1.71 g of the title compound was obtained by treating 2.28 g of5,10-dihydro-5-methoxymethyl-10H-pyrazino[2,3-b][1,4]quinoxaline withethyl bromoacetate by the same method as the one of Example 788.

¹H-NMR(CDCl₃) δ ppm: 3.46(s, 3H), 3.78(s, 3H), 4.49(s, 2H), 5.18(s, 2H),6.26(m, 1H), 6.70-6.79(m, 3H), 7.16(s, 2H)

Examples

The following compounds were obtained by treating the compounds obtainedin Examples 844, 794 and 795 by the same method as the one of Example 2.

Ex. Structural formula NMR 845

¹H-NMR(DMSO-d₆) δ ppm: 3.29(s, 3H), 3.52(q, J=7Hz, 2H), 3.74(t, J=7Hz,2H), 4.84(t, J=7Hz, 1H), 5.05(s, 2H), 6.61-6.72(m, 4H), 7.08(s, 1H),7.16(s, 1H) 846

¹H-NMR(CDCl₃) δ ppm: 1.60-1.79(m, 4H), 2.64(br.s, 1H), 3.43(s, 3H),3.68- 3.78(m, 4H), 5.13(s, 2H), 6.48(d, J=8Hz, 1H), 6.66-6.76(m, 3H),7.07(d, J=3Hz, 1H), 7.12(d, J=3Hz, 1H) 847

¹H-NMR(CDCl₃) δ ppm: 3.45(s, 3H), 4.15(br.m, 2H), 4.37(br.s, 2H),5.13(s, 2H), 5.75(ttd, J=1, 4, 16Hz, 1H), 5.90(ttd, J=1, 5, 16Hz, 1H),6.43(m, 1H), 6.68(m, 3H), 7.11(d, J=3Hz, 1H), 7.16(d, J=3Hz, 1H)

Examples

The following compounds were obtained by treating the compounds obtainedin Examples 845, 846 and 847 by the same method as the one of Example 8.

Ex. Structural formula MS M. p. NMR 848

ESI (+) 229 (MH⁺) 197-204° C. ¹H-NMR(DMSO-d₆) δ ppm: 3.46(t, J=7Hz, 2H),3.62(t, J=7Hz, 2H), 6.30(d, J=8Hz, 1H), 6.47-6.55(m, 3H), 6.83(d, J=3Hz,1H), 6.90(d, J=3Hz, 1H), 9.03(s, 1H) 849

ESI (+) 257 (MH⁺) 138-139° C. ¹H-NMR(CDCl₃) δ ppm: 1.51-1.69(m, 4H),2.58(br.s, 1H), 3.59(t, J=7Hz, 2H), 3.68(m, 2H), 6.14(d, J=8Hz, 1H),6.35(d, J=8Hz, 1H), 6.48-6.60(m, 2H), 6.80(s, 1H), 6.93(s, 1H) 850

ESI (+) 255 (MH⁺) 197-199° C. ¹H-NMR(CDCl₃) δ ppm: 3.88(dd, J=5, 6Hz,2H), 4.16(d, J=4Hz, 2H), 4.69(d, J=6Hz, 1H), 5.43(td, J=5, 16Hz, 1H),5.77(td, J=4, 16Hz, 1H), 6.30-6.38(m, 2H), 6.47- 6.52(m, 2H), 6.84(d,J=3Hz, 1H), 6.90(d, J=3Hz, 1H)

Example 8515,10-Dihydro-10-(3-chloropropan-1-yl)-5-methoxymethyl-10H-pyrazino[2,3-b][1,4]quinoxaline

0.607 g of the title compound was obtained by treating 0.684 g of5,10-dihydro-5-methoxymethoxy-10H-pyrazino[2,3-b][1,4]quinoxaline with3-bromo-1-chloropropane by the same method as the one of Example 788.

¹H-NMR(CDCl₃) δ ppm: 2.33(quint, J=7 Hz, 2H), 3.45(s, 3H), 3.67(t, J=7Hz, 2H), 3.86(t, J=7 Hz, 2H), 5.13(s, 2H), 6.55(d, J=8 Hz, 1H),6.70-6.78(m, 3H), 7.08-7.15(m, 2H)

Example 8525,10-Dihydro-10-(3-azidopropai-1-yl)-5-methoxymethyl-10H-pyrazino[2,3-b][1,4]quinoxaline

To a solution of 0.082 g of5,10-dihydro-10-(3-chloropropan-1-yl)-5-methoxymethyl-10H-pyrazino[2,3-b][1,4]quinoxalinein N,N-dimethylformamide (5 ml) was added in a nitrogen atmosphere 0.035g of sodium azide and the resulting mixture was heated to 80° C. for 1hour. Then the reaction mixture was distributed into ethyl acetate andwater and the aqueous layer was extracted with ethyl acetate. Theorganic layers were combined, washed with water and dried over anhydrousmagnesium sulfate. After distilling off the solvent under reducedpressure, the residue was purified by silica gel column chromatography(eluted with n-hexane/ethyl acetate) to thereby give 0.045 g of thetitle compound as a yellow solid.

¹H-NMR(CDCl₃) δ ppm: 1.83(quint, J=7 Hz, 2H), 3.38(s, 3H), 3.39(t, J=7Hz, 2H), 3.73(t, J=7 Hz, 2H), 5.07(s, 2H), 6.43(d, J=8 Hz, 1H), 6.61(m,3H), 7.02(s, 1H), 7.08(s, 1H)

Example 8535,10-Dihydro-10-(3-aminopropan-1-yl)-5-methoxymethyl-10H-pyrazino[2,3-b][1,4]quinoxaline

0.045 g of5,10-dihydro-10-(3-azidopropan-1-yl)-5-methoxymethyl-10H-pyrazino[2,3-b][1,4]quinoxalinewas dissolved in ethanol (10 ml) and 0.020 g of 10% palladium-carbon wasadded thereto. Then the mixture was subjected to a hydrogenationreaction at room temperature under atmospheric pressure for 24 hours.Next, the reaction mixture was filtered through celite and concentratedunder reduced pressure to thereby give 0.018 g of the title compound asa yellow solid.

¹H-NMR(CDCl₃) δ ppm: 2.15(quint, J=7 Hz, 2H), 2.89(t, J=7 Hz, 2H),3.44(s, 3H), 3.83(br.m, 2H), 5.13(s, 2H), 6.45(dd, J=2, 8 Hz, 1H),6.90-6.97(m, 3H), 7.02(d, J=2 Hz, 1H), 7.10(d, J=2 Hz, 1H)

Example 8545,10-Dihydro-5-(3-aminopropan-1-yl)-10H-pyrazino[2,3-b][1,4]quinoxaline

0.011 g of the title compound was obtained as a yellowish green solid bytreating 0.018 g of5,10-dihydro-5-methoxymethyl-10-(3-aminopropan-1-yl)-10H-pyrazino[2,3-b][1,4]quinoxalineby the same method as the one of Example 8.

¹H-NMR(DMSO-d₆) δ ppm: 1.51(quint, J=7 Hz, 2H), 2.58(t, J=7 Hz, 2H),3.59(t, J=7 Hz, 2H), 6.30(d, J=8 Hz, 1H), 6.47-6.52(m, 3H), 6.80(d, J=3Hz, 1H), 6.89(d, J=3 Hz, 1H), 9.00(s, 1H)

Examples

The following compounds were obtained by treating the compounds obtainedin Examples 811 and 845 by the same method as the one of Example 1237.

Ex. Structural formula NMR 855

¹H-NMR(CDCl₃) δ ppm: 3.05(s, 3H), 3.38(s, 3H), 4.60(s, 2H), 5.08(s, 2H),6.32(d, J=8Hz, 1H), 6.74- 6.77(m, 2H), 7.03(s, 1H), 7.10(s, 1H),7.36-7.66(m, 2H), 7.75-7.79(m, 2H) 856

¹H-NMR(CDCl₃) δ ppm: 3.38(s, 3H), 3.92(m, 2H), 3.96(m, 2H), 5.07(s, 2H),6.66- 6.71(m, 4H), 6.95(d, J=3Hz, 1H), 6.97(d, J=3Hz, 1H), 7.64(dd, J=2,5Hz, 2H), 7.75(dd, J=2, 5Hz, 2H)

Examples

The following compounds were obtained by treating the compounds obtainedin Examples 855 and 856 by the same method as the one of Example 1239.

Ex. Structural formula NMR 857

¹H-NMR(CDCl₃) δ ppm: 3.12(s, 3H), 3.46(s, 3H), 3.70(s, 2H), 5.17(s, 2H),6.42(d, J=8Hz, 1H), 6.68(d, J=2Hz, 1H), 6.71(dd, J=2, 8Hz, 1H), 7.09(d,J=3Hz, 1H), 7.18(d, J=3Hz, 1H) 858

¹H-NMR(CDCl₃) δ ppm: 2.15(quint, J=7Hz, 2H), 2.89(t, J=7Hz, 2H), 3.44(s,3H), 3.83(br.m, 2H), 5.13(s, 2H), 6.45(dd, J=2, 8Hz, 1H), 6.90-6.97(m,3H), 7.02(d, J=2Hz, 1H), 7.10(d, J=2Hz, 1H)

Examples

The following compounds were obtained by treating the compounds obtainedin Examples 857 and 858 by the same method as the one of Example 8.

Ex. Structural formula MS M. p. NMR 859

ESI (+) 228 (MH⁺) 117-122° C. ¹H-NMR(DMSO-d₆) δ ppm: 2.93(s, 3H),3.54(s, 2H), 6.33(d, J=2Hz, 1H), 6.41(d, J=8Hz, 1H), 6.56(dd, J=2, 8Hz,1H), 6.85(d, J=3Hz, 1H), 6.94(d, J=3Hz, 1H), 9.16(s, 1H) 860

ESI (+) 228 (MH⁺) ¹H-NMR(DMSO-d₆) δ ppm: 2.86-2.94(m, 2H), 3.85(t,J=7Hz, 2H), 6.42(dd, J=4, 7Hz, 1H), 6.56-6.60(m, 2H), 6.67(dd, J=4, 7Hz,1H), 6.86(d, J=3Hz, 1H), 6.92(d, J=3Hz, 1H), 8.02(br.s, 2H), 9.47(br.s,1H)

Example 861N-[(5,10-Dihydro-10-methyl-10H-pyrazino[2,3-b][1,4]quinoxalin-7-yl)-(piperidin-2-yl)methyl]phthalimide

The title compound was obtained by treating(5,10-dihydro-5-methoxymethyl-10-methyl-10H-pyrazino[2,3-b][1,4]quinoxalin-7-yl)-(pyridin-2-yl)methanolwith phthalimide by the same method as the one of Example 1237 followedby the same treatment as the one of Example 8.

¹H-NMR(CDCl₃) δ ppm: 2.93(s, 3H), 6.30(s, 1H), 6.42-6.45(m, 2H), 6.61(d,J=8 Hz, 1H), 6.84(d, J=3 Hz, 1H), 6.95(d, J=3 Hz, 1H), 7.23(d, J=8 Hz,1H), 7.28(dd, J=5, 8 Hz,1H), 7.52-7.63(m, 2H), 7.77(t, J=8 Hz, 1H),7.87(m, 2H), 8.45(d, J=5 Hz, 1H), 9.02(s, 1H)

Example 8625,10-Dihydro-5-methyl-8-[(pyridin-2-yl)(amino)methyl]-10H-pyrazino[2,3-b][1,4]quinoxaline

The title compound was obtained by treatingN-[(5,10-dihydro-10-methyl-10H-pyrazino[2,3-b][1,4]quinoxalin-7-yl)-(pyridin-2-yl)methyl]phthalimidewith hydrazine by the same method as the one of Example 1239.

¹H-NMR(DMSO-d₆) δ ppm: 2.22(br.s, 2H), 2.91(s, 3H), 4.81(s, 1H), 6.35(d,J=8 Hz, 1H), 6.40(s, 1H), 6.58(d, J=8 Hz, 1H), 6.81(d, J=4 Hz, 1H),6.91(d, J=4 Hz, 1H), 7.19(dd, J=6, 8 Hz, 1H), 7.38(d, J=8 Hz, 1H),7.70(t, J=8 Hz, 1H), 8.44(d, J=6 Hz, 1H), 8.99(s, 1H)

MS: ESI(+)305(MH⁺)

m.p.: >275° C.

Example 863N-[2-(5,10-Dihydro-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]quinoxalin-5-yl)ethyl]urea

To a solution of 0.081 g of5,10-dihydro-5-(2-aminoethan-1-yl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]quinoxaline in dry tetrahydrofuran (10 ml) were added in anitrogen atmosphere 0.081 ml of triethylamine and 0.061 ml oftrimethylsilyl isocyanate and the resulting mixture was stirred at roomtemperature for 16 hours. Next, the reaction mixture was distributedinto ethyl acetate and water. The organic layer was washed with asaturated aqueous solution of sodium chloride and dried over anhydrousmagnesium sulfate. After distilling off the solvent under reducedpressure, the residue was purified by silica gel column chromatography(eluted with dichloromethane/methanol) to thereby give 0.057 g of thetitle compound as a yellow solid.

¹H-NMR(CDCl₃) δ ppm: 3.40(m, 2H), 3.46(s, 3H), 3.84(t, J=7 Hz, 2H),5.14(s, 2H), 6.64-6.68(m, 1H), 6.73-6.80(m, 3H), 7.10(d, J=3 Hz, 1H),7.14(d, J=3 Hz, 1H)

Example 864N-[(5,10-Dihydro-5-methoxymethyl-10-methyl-10H-pyrazino[2,3-b][1,4]quinoxalin-7-yl)methyl]urea

0.034 g of the title compound was obtained by treating 0.041 g of5,10-dihydro-5-methoxymethyl-10-methyl-7-aminomethyl-10H-pyrazino[2,3-b][1,4]quinoxalineby the same method as the one of Example 863.

¹H-NMR(DMSO-d₆) δ ppm: 3.02(s, 3H), 3.30(s, 3H), 3.96(d, J=6 Hz, 2H),5.06(s, 2H), 5.48(s, 2H), 6.28(t, J=6 Hz, 1H), 6.54(d, J=8 Hz, 1H),6.56(d, J=2 Hz, 1H), 6.65(dd, J=2, 8 Hz, 1H), 7.09(d, J=3 Hz, 1H),7.18(d, J=3 Hz, 1H)

Examples

The following compounds were obtained by treating the compounds obtainedin Examples 863 and 864 by the same method as the one of Example 8.

Ex. Structural formula MS M. p. NMR 865

ESI (+) 271 (MH⁺) >275° C. ¹H-NMR(DMSO-d₆) δ ppm: 2.94(s, 3H), 3.85(d,J=6Hz, 2H), 5.46(s, 2H), 6.21(t, J=6Hz, 1H), 6.26(s, 1H), 6.35(d, J=8Hz,1H), 6.43(d, J=8Hz, 1H), 6.83(d, J=4Hz, 1H), 6.93(d, J=4Hz, 1H), 9.08(s,1H) 866

ESI (+) 293 (MNa⁺) 231-233° C. ¹H-NMR(DMSO-d₆) δ ppm: 3.04(q, J=7Hz,2H), 3.54(t, J=7Hz, 2H), 5.49(s, 2H), 6.19(t, J=7Hz, 1H), 6.32(m, 1H),6.51(m, 2H), 6.72(m, 1H), 6.84(d, J=4Hz, 1H), 6.90(d, J=4Hz, 1H),9.03(s, 1H)

Example 867N-[(5,10-Dihydro-5-methyl-10H-pyrazino[2,3-b][1,4]quinoxalin-8-yl)methyl]guanidine

To a solution of 0.084 g of5,10-dihydro-5-methyl-8-aminomethyl-10H-pyrazino[2,3-b][1,4]quinoxalinein methanol (10 ml) was added 0.046 g of formamidinesulfonic acid andthe resulting mixture was stirred at room temperature for 40 hours.After adding water, the precipitate thus formed was taken up byfiltration to thereby give 0.066 g of the title compound as a yellowsolid.

¹H-NMR(DMSO-d₆) δ ppm: 2.92(s, 3H), 4.03(s, 2H), 6.26(d, J=1 Hz, 1H),6.40(d, J=8 Hz, 1H), 6.48(dd, J=1, 8 Hz, 1H), 6.85(d, J=3 Hz, 1H),6.94(d, J=3 Hz, 1H)

m.p.: >275° C.

MS: ESI(+)270(MH⁺)

Example 868N-[2-(5,10-Dihydro-10H-pyrazino[2,3-b][1,4]quinoxalin-5-yl)ethyl]guanidine

Starting with 0.064 g of5,10-dihydro-5-(2-aminoethan-1-yl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]quinoxaline,0.030 g of the title compound was obtained by the same method as the oneof Example 867.

¹H-NMR(DMSO-d₆) δ ppm: 3.22(t, J=7 Hz, 2H), 3.66(t, J=7 Hz, 2H), 6.33(m,1H), 6.50-6.62(m, 3H), 6.81(d, J=4 Hz, 1H), 6.92(d, J=4 Hz, 1H)

MS: ESI(+)270(MH⁺)

Examples

The following compounds were obtained by the same method as the one ofProduction Example 165.

Ex. Structural formula NMR 869

¹H-NMR(CDCl₃) δ ppm: 1.83(s, 3H), 3.03(s, 3H), 3.31(s, 3H), 4.03(d,J=6Hz, 2H), 5.06(s, 2H), 6.54(d, J=8Hz, 1H), 6.56(d, J=2Hz, 1H),6.63(dd, J=2, 8Hz, 1H), 7.10(d, J=3Hz, 1H), 7.18(d, J=3Hz, 1H),8.24(br.s, 1H) 870

¹H-NMR(CDCl₃) δ ppm: 1.90(s, 3H), 3.39(s, 3H), 3.81(br.t, J=6Hz, 2H),4.25(br.t, J=4Hz, 2H), 5.07(s, 2H), 5.55-5.67(m, 2H), 6.53(m, 1H), 6.61-6.66(m, 3H), 7.04(d, J=3Hz, 1H), 7.08(d, J=3Hz, 1H)

Examples

The following compounds were obtained by the same method as the one ofExample 8.

Ex. Structural formula MS M.p. NMR 871

ESI (+) 270 (MH⁺) 247-249° C. ¹H-NMR(DMSO-d₆) δ ppm: 2.48(s, 3H),2.93(s, 3H), 3.93(d, J=6Hz, 2H), 6.25(s, 1H), 6.37(d, J=8Hz, 1H),6.43(d, J=8Hz, 1H), 6.85(d, J=4Hz, 1H), 6.92(d, J=4Hz, 1H), # 8.19(br.s,1H), 9.05(s, 1H) 872

ESI (+) 318 (MH⁺) 225-227° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.77(s, 3H),3.63(t, J=6Hz, 2H), 4.16(d, J=3Hz, 2H), 5.49(td, J=3, 15Hz, 1H),5.53(td, J=6, 15Hz, 1H), 6.31-6.36(m, 2H), 6.47-6.51(m, 2H), # 6.85(d,J=3Hz, 1H), 6.91(d, J=3Hz, 1H), 7.96(t, J=6Hz, 1H), 9.06(s, 1H)

Example 873N-[2-(5,10-Dihydro-10H-pyrazino[2,3-b][1,4]quinoxalin-5-yl)ethyl]methylsulfonamide

The title compound was obtained by successively treating5,10-dihydro-5-(2-aminoethan-1-yl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]quinoxalineby the same methods as those of Examples 316 and 8.

¹H-NMR(DMSO-d₆) δ ppm: 2.92(s, 3H), 3.06(q, J=7 Hz, 2H), 3.65(t, J=7 Hz,2H), 6.34(m, 1H), 6.53(m, 3H), 6.86(d, J=3 Hz, 1H), 6.93(d, J=3 Hz, 1H),7.26(t, J=7 Hz, 1H), 9.07(s, 1H)

MS: ESI(+)306(MH⁺)

m.p.: 218-222° C.

Example 874[4-(5,10-Dihydro-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]-quinoxalin-5-yl)butan-1-yl]methylsulfonate

Starting with 0.195 g of4-(5,10-dihydro-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]-quinoxalin-5-yl)butan-1-ol,0.247 g of the title compound was obtained as a yellow oily substance bythe same method as the one of Production Example 52.

¹H-NMR(CDCl₃) δ ppm: 1.62-1.71(m, 2H), 1.83-1.92(quint, J=7 Hz, 2H),3.01(s, 3H), 3.45(s, 3H), 3.64(m, 2H), 4.30(t, J=7 Hz, 2H), 5.13(s, 2H),6.43(d, J=8 Hz, 1H), 6.65-6.77(m, 3H), 7.08(d, J=3 Hz, 1H), 7.12(d, J=3Hz, 1H)

Example 875N-[4-(5,10-Dihydro-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]-quinoxalin-5-yl)butyl]-p-toluenesulfonamide

A solution of 0.089 g of p-toluenesulfonamide in N,N-dimethylformamide(5 ml) was cooled to 0° C. in a nitrogen atmosphere. After adding 0.023g of sodium hydride (60% oily), 0.131 g of[4-(5,10-dihydro-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]-quinoxalin-5-yl)butan-1-yl]methanesulfonatewas further added thereto and the resulting mixture was heated to 60° C.for 16 hours. Then the reaction mixture was distributed into ethylacetate and water. The organic layer was washed with a saturated aqueoussolution of sodium chloride and dried over anhydrous magnesium sulfate.After distilling off the solvent under reduced pressure, the residue waspurified by silica gel column chromatography (eluted withdichloromethane/methanol) to thereby give 0.094 g of the title compoundas a yellow solid.

¹H-NMR(CDCl₃) δ ppm: 2.41(s, 3H), 3.05(quint, J=7 Hz, 2H), 3.44(s, 3H),3.55(m, 2H), 3.74(m, 1H), 4.71(br.s, 4H), 5.13(s, 2H), 6.41(d, J=8 Hz,1H),6.68-6.75(m,3H),7.25-7.30(m,4H),7.64(d, J=8 Hz,2H)

Example 876N-[4-(5,10-Dihydro-10H-pyrazino[2,3-b][1,4]quinoxalin-5-yl)butyl]-p-toluenesulfonamide

0.051 g of the title compound was obtained as a yellow solid by treating0.094 g ofN-[4-(5,10-dihydro-10-methoxymethyl-10H-pyrazino[2,3-b]1,4]quinoxalin-5-yl)butyl]-p-toluenesulfonamideby the same method as the one of Example 8.

¹H-NMR(DMSO-d₆) δ ppm: 1.39(m, 4H), 2.35(s, 3H), 2.71(m, 2H), 3.47(m,2H), 6.32(m, 1H), 6.41(m, 1H), 6.48-6.54(m, 2H), 6.80(d, J=3 Hz, 1H),6.88(d, J=3 Hz, 1H), 7.35(d, J=8 Hz, 2H), 7.52(t, J=6 Hz, 1H), 7.63(d,J=8 Hz, 2H), 9.10(br.s, 1H) m.p.: 124-128° C.

Example 8775-Methoxymethyl-5,10-dihydro-7-iodo-10-methyl-10H-pyrazino-[2,3-b][1,4]quinoxaline

7.3 g of the title compound was obtained as a yellow solid by reacting10.0 g of5,10-dihydro-7-iodo-10-methyl-10H-pyrazino[2,3-b][1,4]quinoxaline withchloromethyl methyl ether by the same method as the one of Example 788.

¹H-NMR(CDCl₃) δ ppm: 3.08(s, 3H), 3.44(s, 3H), 5.10(s, 2H), 6.17(d, J=9Hz, 1H), 6.95(d, J=2 Hz, 1H), 7.05(dd, J=2, 9 Hz, 1H), 7.12(d, J=3 Hz,1H), 7.21(d, J=3 Hz, 1H)

Example 8785,10-Dihydro-5-methoxymethyl-10-methyl-7-(pyridin-2-yl)-10H-pyrazino[2,3-b][1,4]quinoxaline

To a solution of (pyridin-2-yl)copper in toluene (20 ml) were added0.423 g of5,10-dihydro-7-iodo-5-methoxymethyl-10-methyl-10H-pyrazino[2,3-b][1,4]quinoxalineand 1.68 g of triphenylphosphine and the resulting mixture was heated to100° C. in a nitrogen atmosphere for 14 hours. After cooling to roomtemperature, the reaction mixture was filtered and distributed intoethyl acetate and water. After filtering off the insoluble matters, theorganic layer was washed with aqueous ammonia and dried over anhydrousmagnesium sulfate. After distilling off the solvent under reducedpressure, the residue was purified by silica gel column chromatography(eluted with n-hexane/ethyl acetate) to thereby give 0.224 g of thetitle compound as a yellow solid.

¹H-NMR(CDCl₃) δ ppm: 3.18(s, 3H), 3.50(s, 3H), 5.28(s, 2H), 6.55(d, J=9Hz, 1H), 7.14(d, J=3 Hz, 1H), 7.10(ddd, J=1, 4, 7 Hz, 1H), 7.14(d, J=3Hz, 1H), 7.33-7.36(m, 2H), 7.54(d, J=8 Hz, 1H), 7.63(dt, J=2, 8 Hz, 1H),8.56(ddd, J=1, 2, 8 Hz, 1H)

Example 8795,10-Dihydro-5-methyl-8-(pyridin-2-yl)-10H-pyrazino[2,3-b][1,4]quinoxaline

The title compound was obtained by treating5,10-dihydro-5-methoxymethyl-10-methyl-7-(pyridin-2-yl)-10H-pyrazino[2,3-b][1,4]quinoxalineby the same method as the one of Example 8.

¹H-NMR(DMSO-d₆) δ ppm: 2.99(s,3H),6.53(d,J=8 Hz,1H),6.89(d,J=4Hz,1H),6.98(d,J=4 Hz,1H),7.16(d,J=2 Hz,1H),7.24(dd,J=5,8Hz,1H),7.28(dd,J=2,8 Hz,1H),7.69(d,J=8 Hz,1H),7.78(dt,J=2,8Hz,1H),8.54(dd,J=2,5 Hz,1H),9.20(s,1 H)

MS: FAB(+)275(M⁺)

Example 8805,10-Dihydro-5-methoxymethyl-10-methyl-7-trimethylsilyl-ethynyl-10H-pyrazino[2,3-b][1,4]quinoxaline

To a solution of 1.445 g of5,10-dihydro-7-iodo-5-methoxymethyl-10-methyl-10H-pyrazino[2,3-b][1,4]quinoxalinein N,N-dimethylformamide (40 ml) were added 0.28 g ofdichlorobis(triphenylphosphine)palladium, 0.090 g of cuprous iodide,0.86 ml of triethylamine and 1.10 ml of trimethylsilylacetylene. Thenthis mixture was treated by the same method as the one of Example 1386-3to thereby give 1.329 g of the title compound as a yellow solid.

¹H-NMR(CDCl₃) δ ppm: 0.23(s, 9H), 3.12(s, 3H), 3.46(s, 3H), 5.15(s, 2H),6.36(d, J=8 Hz, 1H), 6.78(d, J=2 Hz, 1H), 6.89(dd, J=2, 8 Hz, 1H),7.12(d, J=3 Hz, 1H), 7.20(d, J=3 Hz, 1H)

Example 8815,10-Dihydro-7-ethynyl-5-methoxymethyl-10-methyl-10H-pyrazino[2,3-b][1,4]quinoxaline

Similar to Example 1418, a solution of 0.338 g of5,10-dihydro-5-methoxymethyl-10-methyl-7-trimethylsilylethynyl-10H-pyrazino[2,3-b][1,4]quinoxalinein dry tetrahydrofuran was treated with 1.5 ml of a 1 M solution oftetra-n-butylammonium fluoride in tetrahydrofuran. Thus 0.250 g of thetitle compound was obtained as a yellow solid.

¹H-NMR(CDCl₃) δ ppm: 3.00(s, 1H), 3.12(s, 3H), 3.45(s, 3H), 5.12(s, 2H),6.38(d, J=8 Hz, 1H), 6.80(s, 1H), 6.91(d, J=8 Hz, 1H), 7.13(s, 1H),7.20(s, 1H)

Example 882 N,N-Dimethyl-3-(5,10-dihydro-5-methyl-10H-pyrazino[2,3-b][1,4]quinoxalin-8-yl)propynylamide

To 5 ml of triethylamine were added in a nitrogen atmosphere 0.115 g of5,10-dihydro-7-ethynyl-5-methoxymethyl-10-methyl-10H-pyrazino[2,3-b][1,4]quinoxaline,0.020 g of dichlorobis (triphenylphosphine)palladium, 0.020 g of cuprousiodide, 0.026 g of triphenylphosphine and 0.044 ml of dimethylcarbamoylchloride and the resulting mixture was heated to 90° C. for 6 hours.After distilling off the solvent under reduced pressure, the residue wasdistributed into ethyl acetate and water and the insoluble matters werefiltered off. After distilling off the solvent under reduced pressure,the residue was purified by silica gel column chromatography (elutedwith dichloromethane/methanol) to thereby give 0.081 g of the titlecompound as a yellow solid.

¹H-NMR(DMSO-d₆) δ ppm: 2.86(s,3H),2.95(s,3H),3.15(s,3H),6.41(d,J=2Hz,1H),6.45(d,J=8 Hz,1H),6.82(dd,J=2,8 Hz,1H),6.92(d,J=3Hz,1H),6.99(d,J=3 Hz,1H),9.25(s,1H)

m.p.: 203-205° C.

MS: ESI(+)316(MNa⁺)

Example 883(5,10-Dihydro-5-methoxymethyl-10-methyl-10H-pyrazino[2,3-b][1,4]quinoxalin-7-yl)propynoicacid

Into a solution of 0.266 g of5,10-dihydro-7-ethynyl-5-methoxymethyl-10-methyl-10H-pyrazino[2,3-b][1,4]quinoxalinein dry tetrahydrofuran (15 ml) was dropped at −78° C. in a nitrogenatmosphere 1.6 ml of a 1.6 M solution of n-butyllithium in hexane. Afterstirring for 1 hour, dry ice was added to the mixture. Then the bulktemperature was elevated to room temperature and the reaction mixturewas distributed into 6 N potassium hydroxide and ethyl acetate. The pHvalue of the aqueous layer was adjusted to 4 with hydrochloric acidfollowed.by extraction with ethyl acetate. The extractant was distilledoff under reduced pressure to thereby give 0.180 g of the title compoundas a yellow solid.

¹H-NMR(CDCl₃) δ ppm: 3.06(s, 3H), 3.32(s, 3H), 5.11(s, 2H), 6.61(d, J=9Hz, 1H), 6.73(d, J=2 Hz, 1H), 7.04(dd, J=2, 9 Hz, 1H), 7.19(d, J=3 Hz,1H), 7.25(d, J=3 Hz, 1H)

Example 884(5,10-Dihydro-10-methyl-10H-pyrazino[2,3-b][1,4]quinoxalin-7-yl)propynoicacid

The title compound was obtained by treating(5,10-dihydro-5-methoxymethyl-10-methyl-10H-pyrazino[2,3-b][1,4]quinoxalin-7-yl)propynoicacid by the same method as the one of Example 9.

¹H-NMR(DMSO-d₆) δ ppm: 2.95(s, 3H), 6.41(d, J=2 Hz, 1H), 6.45(d, J=8 Hz,1H), 6.84(dd, J=2, 8 Hz, 1H), 6.93(d, J=3 Hz, 1H), 7.00(d, J=3 Hz, 1H)

MS: ESI(+)267(MH⁺)

m.p.: >275° C.

Examples

The following compounds were synthesized by treating5,10-dihydro-5-methoxymethyl-7-iodo-10-methyl-10H-pyrazino[2,3-b][1,4]quinoxalineby the same method as the one of Example 883.

Ex. Stuctural formula NMR 885

¹H-NMR(CDCl₃) δ ppm: 3.06(s, 3H), 3.38(s, 3H), 4.40(s, 2H), 5.06(s, 2H),6.38(d, J=8Hz, 1H), 6.77(d, J=2Hz, 1H), 6.86(dd, J=2, 8Hz, 1H), 7.14(d,J=3Hz, 1H), 7.21(d, J=3Hz, 1H) 886

¹H-NMR(CDCl₃) δ ppm: 3.12(s, 3H), 3.48(s, 3H), 5.17(s, 2H), 6.42(d,J=8Hz, 1H), 6.86(d, J=2Hz, 1H), 6.96(dd, J=2, 8Hz, 1H), 7.14(d, J=3Hz,1H), 7.21(d, J=3Hz, 1H), 7.30-7.35(m, 3H), 7.49- 7.52(m, 2H) 887

¹H-NMR(CDCl₃) δ ppm: 2.37(s, 6H), 3.12(s, 3H), 3.42(s, 2H), 3.44(s, 3H),5.13(s, 2H), 6.37(d, J=8Hz, 1H), 6.77(d, J=2Hz, 1H), 6.86(dd, J=2, 8Hz,1H), 7.12(d, J=3Hz, 1H), 7.20(d, J=3Hz, 1H) 888

¹H-NMR(CDCl₃) δ ppm: 1.25(t, J=7Hz, 3H), 3.13(s, 3H), 3.43(s, 3H),4.09(q, J=7Hz, 2H), 5.10(s, 2H), 6.40(d, J=8Hz, 1H), 6.66(s, 1H),7.02(d, J=8Hz, 1H), 7.16(d, J=3Hz, 1H), 7.22(d, J=3Hz, 1H)

Examples

The following compounds were obtained by treating the compounds obtainedin Examples 885, 886 and 887 by the same method as the one of Example 8.

Ex. Structural formula Ms M.p. NMR 889

ESI (+) 253 (MH⁺) 241-243° C. ¹H-NMR(DMSO-d₆) δ ppm: 2.93(s, 3H),4.21(d, J=7Hz, 2H), 5.24(t, J=7Hz, 1H), 6.31(d, J=2Hz, 1H), 6.38(d,J=8Hz, 1H), 6.61(dd, J=2, 8Hz, 1H), 6.88(d, J=3Hz, 1H), 6.97(d, J=3Hz,1H), 9.16(s, 1H) 890

ESI (+) 299 (MH⁺) 245-247° C. ¹H-NMR(CDCl₃) δ ppm: 3.09(s, 3H),6.24(br.s, 1H), 6.35(d, J=2Hz, 1H), 6.35(d, J=8Hz, 1H), 6.85(dd, J=2,8Hz, 1H), 6.96(d, J=4Hz, 1H), 7.11(d, J=4Hz, 1H), 7.30-7.35(m, 3H),7.46-7.49(m, 2H) 891

ESI (+) 280 (MH⁺) 188-189° C. ¹H-NMR(DMSO-d₆) δ ppm: 2.19(s, 6H),2.92(s, 3H), 3.38(s, 2H), 6.32(s, 1H), 6.39(d, J=8Hz, 1H), 6.63(d,J=8Hz, 1H), 6.87(d, J=3Hz, 1H), 6.93(d, J=3Hz, 1H), 9.12(s, 1H)

Example 892Ethyl(5,10-dihydro-50-methyl-10H-pyrazino[2,3-b][1,4]quinoxalin-8-yl)propynoate

The following compound was obtained by treatingethyl(5,10-dihydro-5-methoxymethyl-10-methyl-10H-pyrazino[2,3-b][1,4]quinoxalin-7-yl)propynoateby the same method as the one of Example 9.

¹H-NMR(DMSO-d₆) δ ppm: 1.24(t, J=7 Hz, 3H), 2.95(s, 3H), 4.18(q, J=7 Hz,2H), 6.41(d, J=2 Hz, 1H), 6.45(d, J=8 Hz, 1H), 6.87(dd, J=2, 8 Hz, 1H),6.93(d, J=3 Hz, 1H), 7.00(d, J=3 Hz, 1H), 9.27(s, 1H)

MS: ESI(+)295(MH⁺)

m.p.: 232-235° C.

Example 893 Ethyl3-(5,10-dihydro-5-methoxymethyl-10-methyl-10H-pyrazino[2,3-b][1,4]quinoxalin-7-yl)-3-oxopropanoate

0.150 g of ethyl3-(5,10-dihydro-5-methoxymethyl-10-methyl-10H-pyrazino[2,3-b][1,4]quinoxalin-7-yl)propynoatewas dissolved in a saturated solution of dimethylamine in ethanol (25ml) and heated under reflux for 1 hour. After distilling off the solventunder reduced pressure, the residue was purified by silica gel columnchromatography (eluted with n-hexane/ethyl acetate) to thereby give0.080 g of the title compound as a yellow solid.

¹H-NMR(CDCl₃) δ ppm: 1.27(t, J=7 Hz, 3H), 3.18(s, 3H), 3.46(s, 3H),3.86(s, 2H), 4.20(q, J=7 Hz, 2H), 5.17(s, 2H), 6.46(d, J=8 Hz, 1H),7.21(d, J=3 Hz, 1H), 7.24-7.26(m, 2H), 7.37(dd, J=2, 8 Hz, 1H)

Example 894 Ethyl3-(5,10-dihydro-5-methoxymethyl-10-methyl-10H-pyrazino-[2,3-b][1,4]quinoxalin-7-yl)-3-(methylthio)propenoate

To a solution of 0.205 g of ethyl3-(5,10-dihydro-5-methoxymethyl-10-methyl-10H-pyrazino[2,3-b][1,4]quinoxalin-7-yl)propynoatein N,N-dimethylformamide (10 ml) were added 1 ml of methanol and 0.063 gof methylmercaptane sodium salt and the resulting mixture was stirred atroom temperature for 1 hour. After distilling off the solvent underreduced pressure, the residue was purified by silica gel columnchromatography (eluted with n-hexane/ethyl acetate) to thereby give0.136 g of the title compound as a reddish oily substance.

¹H-NMR(DMSO-d₆) δ ppm: 1.12 and 1.29(t, J=7 Hz, total 3H), 2.13 and2.37(s, total 3H), 3.07(s, 3H), 3.30 and 3.32(s, total 3H), 3.94 and4.07(q, J=7 Hz, total 2H), 5.03 and 5.13(s, total 2H), 5.53 and 5.87(s,total 1H), 6.52-6.73(m, 3H), 7.15 and 7.16(d, J=3 Hz, total 1H), 7.23(d,J=3 Hz, 1H)

Example 895 Ethyl3-(5,10-dihydro-5-methoxymethyl-10-methyl-10H-pyrazino-[2,3-b][1,4]quinoxalin-7-yl)-3-(methylsulfinyl)propenoate

To a solution of 102 mg of ethyl3-(5,10-dihydro-5-methoxymethyl-10-methyl-10H-pyrazino[2,3-b][1,4]quinoxalin-7-yl)-3-(methylthio)propenoatein dichloromethane (10 ml) were added 0.120 g of m-chloroperbenzoic acidand 0.025 g of sodium hydrogencarbonate and the resulting mixture wasstirred at room temperature for 20 hours. Then the reaction mixture wasdistributed into ethyl acetate and water. Next, the organic layer wasdried over anhydrous magnesium sulfate and distilled off under reducedpressure to thereby give 0.150 g of the crude title compound as a redoily substance.

¹H-NMR(CDCl₃) δ ppm: 1.18 and 1.26(t, J=7 Hz, total 3H), 2.42 and2.80(s, total 3H), 3.06(s, 3H), 3.37 and 3.38(s, total 3H), 4.10 and4.17(q, J=7 Hz, total 2H), 4.98-5.13(m, 2H), 6.21 and 6.22(s, total 1H),6.40 and 6.41(d, J=8 Hz, total 1H), 6.57 and 6.73(d, J=2 Hz, total 1H),6.67 and 6.85(dd, J=2, 8 Hz, total 1H), 7.08 and 7.10(d, J=3 Hz, total1H), 7.15 and 7.17(d, J=3 Hz, total 1H)

Examples

The following compounds were obtained by treating the compounds obtainedin Examples 893 and 895 by the same method as the one of Example 9.

Ex. Structural formula MS M.p. NMR 896

88-89° C. ¹H-NMR(CDCl₃) δ ppm: 1.16(t, J=7Hz, 3H), 3.11(s, 3H), 3.80(s,2H), 4.20(q, J=7Hz, 2H), 6.35(d, J=8Hz, 1H), 6.77(d, J=2Hz, 1H), 7.01(d,J=3Hz, 1H), 7.11(d, J=3Hz, 1H), 7.21(dd, J=2, 8Hz, 1H), 7.25(br.s, 1H)897

FAB (+) 359 (MH⁺) ¹H-NMR(CDCl₃) δ ppm: 1.25 and 1.32(t, J=7Hz, total3H), 2.47 and 2.86(s, total 3H), 3.06 and 3.07(s, total 3H), 4.17 and4.23(q, J=7Hz, total 2H), 6.16 and 6.24(s, total 1H), 6.35- 6.41(m, 2H),6.62 and 6.71(m, 1H), 6.95 and # 6.98(d, J=3Hz, total 1H), 7.09 and7.12(d, J=3Hz, total 1H)

Example 898 Ethyl3-(5,10-dihydro-5-methyl-10H-pyrazino[2,3-b][1,4]quinoxalin-8-yl)-3-(methylthio)propenoate

The title compound was obtained by treating ethyl3-(5,10-dihydro-5-methoxymethyl-10-methyl-10H-pyrazino[2,3-b][1,4]quinoxalin-7-yl)-3-(methylthio)propenoateby the same method as the one of Example 8.

¹H-NMR(CDCl₃) δ ppm: 1.20 and 1.27(t, J=7 Hz, total 3H), 2.05 and2.36(s, total 3H), 3.07 and 3.08(s, total 3H), 4.06 and 4.21(q, J=7 Hz,total 2H), 5.53 and 5.59(s, total 1H), 6.15 and 6.19(d, J=2 Hz, total1H), 6.38(d, J=2 Hz, 1H), 6.59 and 6.64(dd, J=2, 8 Hz, total 1H), 6.91and 6.95(d, J=3 Hz, total 1H), 7.07 and 7.11(d, J=3 Hz, total 1H)

Example 899 6-Methyl-10H-pyrazino[2,3-b][1,4]benzothiazine

To a solution of 0.737 g of2-(6-methyl-2-nitrophenyl)thio-3-chloropyrazine in 15 ml oftetrahydrofuran was added a solution of 4.2 g of hydrosulfite sodium inwater (8.4 ml). Into the reaction mixture was dropped a solution of 4.2ml of aqueous ammonia with 4.2 ml of water under ice-cooling. Afterstirring at room temperature for 20 hours, the reaction mixture wasdistributed into ethyl acetate and water and the organic layer was driedover anhydrous magnesium sulfate. After distilling off the solvent underreduced pressure, 0.676 g of a crude amine was obtained. This amine wasdissolved in 10 ml of N,N-dimethylformamide. The reaction mixture wasdegassed and heated to 80° C. for 2 hours. Then the reaction mixture wasdistributed into ethyl acetate and water. The organic layer was washedwith. water and dried over anhydrous magnesium sulfate. After distillingoff the solvent under reduced pressure, the residue was purified bysilica gel column chromatography (eluted with n-hexane/ethyl acetate) tothereby give 0.105 g of the title compound as a yellow solid.

¹H-NMR(DMSO-d₆) δ ppm: 2.07(s, 3H), 6.58(d, J=8 Hz, 1H), 6.65(d, J=8 Hz,1H), 6.85(t, J=8 Hz, 1H), 7.60(d, J=3 Hz, 1H), 7.61(d, J=3 Hz, 1H),9.40(s, 1H)

MS: FAB(+)215(M⁺)

m.p.: 165-166° C.

Example 90010-Methoxymethyl-8-[N-(pyridin-3-yl)aminomethyl]-10H-pyrazino-[2,3-b][1,4]benzothiazine

3 g of(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbaldehydeand 3.4 g of 3-aminopyridine were dissolved in toluene and heated underreflux for 2 hours. During this period, the water formed in the reactionsystem was eliminated by using a Dean-Stark tube. After the completionof the reaction, the toluene was distilled off under reduced pressureand the residue was dissolved in ethanol and tetrahydrofuran newly addedthereto. After adding 4.06 g of sodium borohydride under ice-cooling,the resulting mixture was stirred at room temperature. After thecompletion of the reaction, the reaction mixture was poured into asaturated aqueous solution of sodium chloride and repeatedly extractedwith ethyl acetate. The extract thus obtained was dried over anhydroussodium. sulfate and filtered. The filtrate was distilled off underreduced pressure and the residue was purified by silica gel columnchromatography (eluted with toluene/acetone) to thereby give 1.35 g ofthe title compound as a yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 3.46(s, 3H), 4.28(s, 2H), 4.30(s, 2H), 5.22(s, 2H),6.83(dd, J=2, 5 Hz, 1H), 6.95(d, J=8 Hz, 1H), 6.97(d, J=8 Hz, 1H),7.12(s, 1H), 7.83(d, J=3 Hz, 2H), 7.98(d, J=5 Hz, 1H), 8.04-8.09(m, 1H)

Example 9018-[N-(Pyridin-3-yl)aminomethyl]-10H-pyrazino[2,3-b][1,4]benzothiazine

0.99 g of the title compound was obtained as yellow crystals bydeblocking 1.35 g of10-methoxymethyl-8-[N-(pyridin-3-yl)aminomethyl]-10H-pyrazino[2,3-b][1,4]benzothiazineobtained in Example 900 by the same method as the one of Example 9.

¹H-NMR(DMSO-d₆) δ ppm: 4.08(d, J=6 Hz, 2H), 6.45(t, J=6 Hz, 1H), 6.74(s,1H), 6.78(d, J=8 Hz, 1H), 6.80(d, J=8 Hz, 1H), 6.84(d, J=8 Hz, 1H),7.02(dd, J=5, 8 Hz, 1H), 7.60(s, 2H), 7.70(d, J=5 Hz, 1H), 7.90(s, 1H),9.49(br.s, 1H)

MS: FAB(+)308(MH⁺)

m.p.: 168-172° C.

Examples

Similar to Example 900,(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]-benzothiazin-8-yl)carbaldehydewas treated with readily available various amines. Then, the productsthus obtained were deblocked by the same method as the one of Example 9to thereby give the following compounds.

Ex. Amine Structural formula MS M.p. NMR 902

ESI(+) 308 (MH⁺) 208- 212° C. ¹H-NMR(DMSO-d₆) δ ppm: 4.25(d, J=6Hz, 2H),6.42-6.48(m, 1H), 6.47(t, J=6Hz, 1H), 6.74(d, J=8Hz, 1H), 6.76(s, 1H),6.82(d, J=8Hz, 1H), 6.94- 7.02(m, 1H), 7.34(d, J=8Hz, 1H), 7.62(s, #2H), 7.90(d, J=5Hz, 1H), 9.50(br.s, 1H) 903

ESI(+) 308 (MH⁺) 194- 196° C. ¹H-NMR(DMSO-d₆) δ ppm: 4.13(d, J=6Hz, 2H),6.44(d, J=6Hz, 2H), 6.72(s, 1H), 6.74(d, J=8Hz, 1H), 7.17(t, J=6Hz, 1H),7.62(s, 2H), 7.87(d, J=8Hz, 1H), 7.98(d, J=5Hz, 2H), 9.52(br.s, 1H) 904

¹H-NMR(DMSO-d₆) δ ppm: 4.28(d, J=5Hz, 2H), 6.72(s, 1H), 6.73(d, J=8Hz,1H), 6.82(d, J=8Hz, 1H), 7.53(t, J=5Hz, 1H), 7.61(s, 1H), 7.60(d, J=2Hz,1H), 7.64(d, J=2Hz, 1H), 7.88(s, 1H), 7.92(s, 1H), 9.48(br.s, 1H) 905

232- 235° C. ¹H-NMR(CDCl₃) δ ppm: 4.48(d, J=5Hz, 1H), 5.70(br.s, 1H),6.52(s, 1H), 6.59(d, J=8Hz, 1H), 6.81(d, J=8Hz, 1H), 6.82(d, J=8Hz, 1H),7.25(d, J=4Hz, 1H), 7.50(d, J=3Hz, 1H), 7.65(d, J=3Hz, 1H), 8.30(d,J=4Hz, 2H), 8.75(br.s, 1H) 906

FAB(+) 313 (M⁺) 230- 235° C. ¹H-NMR(DMSO-d₆) δ ppm: 4.22(d, J=6Hz, 2H),6.60(d, J=5Hz, 1H), 6.66(d, J=8Hz, 1H), 6.67(s, 1H), 6.84(d, J=8Hz, 1H),6.98(d, J=5Hz, 1H), 7.60(d, J=3Hz, 1H), 7.61(d, J=3Hz, 1H), # 7.99(t,J=6Hz, 1H), 9.50(br.s, 1H) 907

ESI(+) 322 (MH⁺) ¹H-NMR(DMSO-d₆) δ ppm: 3.92(s, 2H), 4.20(br.s, 2H),5.28-5.33(m, 1H), 6.32(d, J=8Hz, 2H), 6.37(d, J=8Hz, 2H), 6.77(s, 1H),6.73- 6.82(m, 2H), 7.62(s, 2H), 9.46(s, 1H) 908

ESI(+) 358 (MH⁺) 160- 164° C. ¹H-NMR(DMSO-d₆) δ ppm: 4.21(d, J=5Hz, 2H),6.80(s, 1H), 6.82(d, J=8Hz, 1H), 6.87(s, 1H), 6.88(d, J=8Hz, 1H),6.84-6.92(m, 1H), 7.26-7.40(m, 2H), 7.58(d, J=5Hz, 1H), 7.60(s, 2H), #7.77(d, J=5Hz, 1H), 8.50(br.s, 1H), 9.50(br.s, 1H) 909

ESI(+) 358 (MH⁺) 222- 225° C. ¹H-NMR(DMSO-d₆) δ ppm: 4.53(d, J=5Hz, 2H),6.75-6.80(m, 1H), 6.78(s, 1H), 6.79(d, J=8Hz, 1H), 6.88(d, J=8Hz, 1H),7.48(t, J=10Hz, 1H), 7.58(s, 2H), 7.55-7.63(m, 1H), 7.69(d, J=10Hz, 1H),# 7.79(d, J=8Hz, 1H), 7.92(t, J=8Hz, 1H), 8.24(d, J=10Hz, 1H),9.45(br.s, 1H) 910

ESI(+) 322 (MH⁺) ¹H-NMR(CDCl₃) δ ppm: 3.62(s, 2H), 3.82(s, 2H),6.30(br.s, 1H), 6.53(s, 1H), 6.77(d, J=8Hz, 1H), 6.85(d, J=8Hz, 1H),7.12- 7.15(m, 1H), 7.26(d, J=7Hz, 1H), 7.62(t, J=7Hz, 1H), 7.70(d,J=3Hz, 2H), 8.55(d, # J=5Hz, 1H), 9.52(br.s, 1H) 911

ESI(+) 322 (MH⁺) 104- 106° C. ¹H-NMR(CDCl₃) δ ppm: 3.68(s, 2H), 3.80(s,2H), 6.52(br.s, 1H), 6.54(s, 1H), 6.78(d, J=8Hz, 1H), 6.83(d, J=8Hz,1H), 7.25- 7.28(m, 2H), 7.57(d, J=3Hz, 1H), 7.69(d, J=3Hz, 1H), 7.66- #7.70(m, 1H), 8.52- 8.55(m, 1H), 8.59(br.s, 1H) 912

ESI(+) 322 (MH⁺) 174- 176° C. ¹H-NMR(CDCl₃) δ ppm: 3.65(s, 2H), 3.80(s,2H), 6.54(s, 1H), 6.67(br.s, 1H), 6.79(d, J=8Hz, 1H), 6.83(d, J=8Hz,1H), 7.22-7.30(m, 3H), 7.55(d, J=3Hz, 1H), 7.68(d, J=3Hz, 1H), 8.58(d,J=5Hz, 2H) 913

ESI(+) 328 (MH⁺) 173- 175° C. ¹H-NMR(DMSO-d₆) δ ppm: 0.83-1.00(m, 2H),1.30-1.50(m, 1H), 1.60(d, J=8Hz, 2H), 2.28(d, J=5Hz, 2H), 2.38(d, J=2,8Hz, 2H), 2.87(d, J=7Hz, 2H), 3.25(br.s, 2H), 3.44(s, 2H), 6.74(d,J=7Hz, 1H), # 6.75(s, 1H), 6.80(d, J=7Hz, 1H), 7.60(d, J=2Hz, 1H),7.61(d, J=2Hz, 1H), 9.48(br.s, 1H) 914

ESI(+) 336 (MH⁺) 179- 182° C. ¹H-NMR(DMSO-d₆) δ ppm: 3.03(t, J=7Hz, 2H),3.10-3.20(m, 2H), 3.30(br.s, 1H), 3.86(br.s, 2H), 6.78(s, 1H), 6.88(d,J=8Hz, 1H), 6.92(d, J=8Hz, 1H), 7.20- 7.32(m, 2H), 7.63(s, 2H),7.68-7.78(m, 1H), # 8.50(d, J=5Hz, 1H), 9.63(br.s, 1H) 915

ESI(+) 336 (MH⁺) 162- 165° C. ¹H-NMR(DMSO-d₆) δ ppm: 2.08(s, 3H),2.17(s, 3H), 4.24(d, J=5Hz, 2H), 6.03(s, 1H), 6.18(s, 1H), 6.70(br.s,1H), 6.73(d, J=8Hz, 1H), 6.75(s, 1H), 6.82(d, J=8Hz, 1H), 7.62(s, 2H),9.48(br.s, 1H) 916

ESI(+) 413 (MH⁺) 180- 184° C. ¹H-NMR(DMSO-d₆) δ ppm: 4.35(d, J=5Hz, 2H),5.12(s, 2H), 6.42- 6.48(m, 1H), 6.53(t, J=5Hz, 1H), 6.72(d, J=8Hz, 1H),6.74(s, 1H), 6.79(d, J=8Hz, 1H), 7.04(d, J=5Hz, 1H), # 7.30-7.36(m, 1H),7.38-7.42(m, 2H), 7.48-7.52(m, 3H), 7.60(s, 2H), 9.48(br.s, 1H) 917

FAB(+) 409 (M⁺) 158- 161° C. ¹H-NMR(CDCl₃) δ ppm: 4.60(d, J=5Hz, 2H),5.64(t, J=5Hz, 1H), 6.50(s, 1H), 6.55(br.s, 1H), 6.80(d, J=8Hz, 1H),6.88(d, J=8Hz, 1H), 7.58(s, 1H), 7.67(s, 1H), 7.69(s, 1H), 8.30(s, 1H)918

245- 250° C. ¹H-NMR(CD₃OD) δ ppm: 4.52(s, 2H), 4.90(br.s, 2H), 6.55(d,J=8Hz, 1H), 6.92(d, J=8Hz, 1H), 6.95(s, 1H), 6.96(s, 1H), 6.97(d, J=8Hz,1H), 7.72(s, 1H), 7.82(d, J=3Hz, 1H), 7.86(d, J=3Hz, 1H), 7.87(d, J=8Hz,1H), 8.53(s, 1H) 919

ESI(+) 366 (MH⁺) 140- 148° C. ¹H-NMR(DMSO-d₆) δ ppm: 3.73(s, 3H),4.16(d, J=5Hz, 2H), 6.71(d, J=8Hz, 1H), 6.74(s, 1H), 6.83(d, J=8Hz, 1H),7.62(s, 2H), 7.82(d, J=8Hz, 2H), 7.85(t, J=5Hz, 1H), 8.55(s, 1H),9.50(br.s, 1H) 920

ESI(+) 336 (MH⁺) 148- 152° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.14(t, J=6Hz, 3H),2.55(q, J=6Hz, 2H), 3.30(s, 2H), 4.20(d, J=5Hz, 1H), 6.42(d, J=3Hz, 1H),6.46(s, 1H), 6.72(s, 1H), 6.73(d, J=8Hz, 1H), 6.88(d, J=8Hz, 1H), #7.60(s, 2H), 7.94(d, J=3Hz, 1H), 9.53(s, 1H) 921

ESI(+) 338 (MH⁺) 156- 160° C. ¹H-NMR(DMSO-d₆) δ ppm: 3.30(t, J=5Hz, 1H),4.15(d, J=5Hz, 2H), 4.36(s, 2H), 6.34(m, 1H), 6.62(s, 1H), 6.65(s, 1H),6.66(d, J=8Hz, 1H), 6.82(d, J=8Hz, 1H), 7.31(m, 1H), # 1H), 7.61(s, 2H),7.92(d, J=5Hz, 1H), 9.52(s, 1H) 922

ESI(+) 336 (MH⁺) 230- 235° C. ¹H-NMR(DMSO-d₆) δ ppm: 2.48(s, 6H),4.05(d, J=6Hz, 2H), 6.14(s, 2H), 6.68(s, 1H), 6.69(d, J=8Hz, 1H),6.84(d, J=8Hz, 1H), 7.62(s, 2H), 7.85(br.s, 1H), 9.50(br.s, 1H)

Examples

The following compounds were obtained by treating(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbaldehydewith various aminopyridines by the same method as the one of Example900.

Amino- Ex. pyridine Structural formula NMR 923

¹H-NMR(CDCl₃) δ ppm: 2.95(s, 6H), 3.43(s, 3H), 4.17(s, 2H), 5.18(s, 2H),6.43(d, J=8Hz, 1H), 6.85-6.90(m, 2H), 6.89(s, 2H), 7.08(s, 1H), 7.66(d,J=2Hz, 1H), 7.77-7.82(m, 2H) 924

¹H-NMR(CDCl₃) δ ppm: 3.48(s, 3H), 4.18(s, 2H), 4.40(s, 1H), 4.50(br.s,2H), 5.22(s, 2H), 6.28(d, J=8Hz, 1H), 6.82(dd, J=2, 5Hz, 1H), 6.93(s,2H), 7.10(s, 1H), 7.20-7.40(m, 2H) 7.60(d, J=2Hz, 1H), 7.81(d, J=3Hz,1H), 7.83(d, J=3Hz, 1H)

Examples

The following compounds were obtained by treating the compounds in theabove table by the same method as the one of Example 9.

Ex. Structural formula MS M.p. NMR 925

ESI (+) 351 (MH⁺) 244-247° C. ¹H-NMR(CDCl₃) δ ppm: 2.95(s, 6H), 4.13(s,2H), 6.45(d, J=7Hz, 1H), 6.45(br.s, 1H), 6.52(s, 1H), 6.80(d, J=8Hz,1H), , 6.83(d, J=8Hz, 1H), 6.92(dd, J=2, 7Hz, 1H), 7.55(d, J=2Hz, 1H),7.71(d, J=2Hz, 1H), 7.72(d, J=2Hz, 1H), 9.50(s, 1H) 926

FAB (+) 413 (MH⁺) 208-211° C. ¹H-NMR(CDCl₃) δ ppm: 4.20(s, 2H), 4.42(s,2H), 4.55(br.s, 2H), 6.30(d, J=8Hz, 1H), 6.82(d, J=5Hz, 1H), 6.95(s,2H), 7.12(s, 1H), 7.20-7.40(m, 5H), 7.62(d, J=2Hz, 1H), 7.81(d, J=3Hz,1H), 7.83(d, J=3Hz, 1H), 9.50(s, 1H) 927

ESI (+) 323 (MH⁺) 225-228° C. ¹H-NMR(DMSO-d₆) δ ppm: 4.09(d, J=6Hz, 2H),5.39(t, J=6Hz, 1H), 5.50(s, 2H), 6.34-6.39(m, 2H), 6.75(s, 1H), 6.76(d,J=8Hz, 1H), 6.85(d, J=8Hz, 1H), 7.24(br.d, J=4Hz, 1H), 7.62(s, 2H),9.52(s, 1H)

Examples

The following compounds were obtained by treating(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbaldehydewith various aminopyridines by the same method as the one of Example900.

Ex. Amine Structural formula NMR 928

¹H-NMR(CDCl₃) δ ppm: 3.46(s, 3H), 3.87(s, 3H), 4.22(s, 2H), 5.22(s, 2H),6.58(d, J=8Hz, 1H), 6.60(d, J=8Hz, 1H), 6.97(s, 1H), 7.02(d, J=8Hz, 1H),7.03(d, J=8Hz, 1H), 7.12(s, 1H), 7.55(d, J=2Hz, 1H), 7.82(d, J=3Hz, 1H),7.84(d, J=3Hz, 1H) 929

¹H-NMR(CDCl₃) δ ppm: 3.34(s, 3H), 3.85(s, 3H), 3.88(s, 3H), 4.10(s, 2H),5.10(s, 2H), 6.03(d, J=8Hz, 1H), 6.05(d, J=8Hz, 1H), 6.62(d, J=8Hz, 1H),6.82(d, J=8Hz, 1H), 6.83(s, 1H), 7.00(s, 1H), 7.52(s, 2H) 930

¹H-NMR(CDCl₃) δ ppm: 1.29(d, J=6Hz, 6H), 3.42(s, 3H), 3.90(br.s, 1H),4.18(s, 2H), 5.02-5.17(m, 1H), 5.18(s, 2H), 6.52(d, J=8Hz, 1H), 6.87(s,2H), 6.88(d, J=8Hz, 1H), 7.06(s, 1H), 7.52(d, J=2Hz, 1H), 7.78(s, 2H)931

¹H-NMR(CDCl₃) δ ppm: 3.47(s, 3H), 4.22(s, 2H), 5.22(s, 2H), 6.73(d,J=7Hz, 1H), 6.95(s, 1H), 6.97(d, J=7Hz, 1H), 7.09(s, 1H), 6.90-7.12(m,5H), 7.32(t, J=7Hz, 2H), 7.62(d, J=2Hz, 1H), 7.82(d, J=3Hz, 1H), 7.83(d,J=3Hz, 1H) 932

¹H-NMR(CDCl₃) δ ppm: 1.23(t, J=7Hz, 3H), 3.43(s, 3H), 3.90(br.s, 1H),4.20(q, J=7Hz, 2H), 4.20(s, 2H), 4.77(s, 2H), 5.21(s, 2H), 6.70(d,J=8Hz, 1H), 6.90(s, 2H), 6.92(dd, J=2, 8Hz, 1H), 7.08(s, 1H), 7.48(d,J=2Hz, 1H), 7.78(d, J=3Hz, 1H), 7.80(d, J=3Hz, 1H)

Examples

The following compounds were obtained by treating the compounds in theabove table by the same method as the one of Example 9.

Ex. Structural formula MS M.p. NMR 933

ESI (+) 338 (MH⁺) 168- 172° C. ¹H-NMR(DMSO-d₆) δ ppm: 3.67(s, 3H),4.02(d, J=5Hz, 2H), 5.93(t, J=5Hz, 1H), 6.56(d, J=7Hz, 1H), 6.77(s, 1H),6.78(d, J=8Hz, 1H), 6.84(d, J=8Hz, 1H), 6.98(d, J=8Hz, 1H), 7.38(s, 1H),7.60(s, 2H), 9.48(br.s, 1H) 934

ESI (+) 368 (MH⁺) 160- 164° C. ¹H-NMR(CDCl₃) δ ppm: 3.82(s, 3H), 3.98(s,3H), 4.15(br.s, 1H), 4.18(s, 2H), 6.17(d, J=7Hz, 1H), 6.47(br.s, 1H),6.52(s, 1H, 6.70(d, J=7Hz, 1H), 6.82(d, J=8Hz, 1H), 6.84(d, J=8Hz, 1H),7.55(s, 1H), 7.68(s, 1H) 935

ESI (+) 366 (MH⁺) 145- 148° C. ¹H-NMR(CDCl₃) δ ppm: 1.30(d, J=6Hz, 6H),3.70- 3.80(m, 1H), 4.18(s, 2H), 5.12(m, 1H), 6.43(br.s, 1H), 6.52(d,J=2Hz, 1H), 6.56(d, J=6Hz, 1H), 6.82(d, (J=8Hz, 1H), 6.85(d, J=8Hz, 1H),6.90-6.95(m, 1H), 7.54(d, J=3Hz, 1H), 7.58(d, J=3Hz, 1H), 7.69(s, 1H)936

ESI (+) 400 (MH⁺) 162- 165° C. ¹H-NMR(CDCl₃) δ ppm: 4.13(s, 2H),6.48(br.s, 1H), 6.74(d, J=8Hz, 1H), 6.76(s, 1H), 6.80(d, J=8Hz, 1H),6.90-7.10(m, 5H), 7.15(br.s, 1H) 7.30(t, J=6Hz, 2H), 7.48(d, J=3Hz, 1H),7.60(d, J=3Hz, 1H), 7.63(d, J=3Hz, 1H) 937

ESI (+) 410 (MH⁺) 230- 235° C. ¹H-NMR(CDCl₃) δ ppm: 1.25(t, J=6Hz, 3H),4.14(s, 2H), 4.21(q, J=6Hz, 2H), 4.79(s, 2H), 6.44(br.s, 1H), 6.51(s,1H), 6.72(d, J=8Hz, 1H), 6.81(d, J=7Hz, 1H), 6.86(d, J=8Hz, 1H),6.95(dd, J=3, 7Hz, 1H), 7.25-7.28(m, 1H), 7.42(d, J=3Hz, 1H), 7.55(d,J=3Hz, 1H), 7.68(d, J=3Hz, 1H)

Examples

The following compounds were obtained by treating(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbaldehyde with various aminopyridines by the same method as the oneof Example 900.

Amino- Ex. pyridine Structural formula NMR 938

¹H-NMR(CDCl₃) δ ppm: 3.37(s, 3H), 4.00 (s, 2H), 4.20(s, 2H),4.23-4.37(br.s, 1H), 5.17(s, 1H), 6.77 (d, J=8Hz, 1H), 6.87(d, J=8Hz,1H), 7.07(s, 1H), 7.10- 7.30(m, 7H), 7.79 (s, 2H), 7.88(d, J=8Hz, 1H),7.97 (s, 1H) 939

¹H-NMR(CDCl₃) δ ppm: 2.95(s, 4H), 3.42(s, 3H), 4.20(s, 2H), 4.36 (br.s,1H), 5.18(s, 2H), 6.75(dd, J=2, 8Hz, 1H), 6.85(d, J=8Hz, 1H), 6.85-7.00(m, 2H), 7.07 (s, 1H), 7.10- 7.30(m, 5H), 7.78 (s, 2H), 7.97(s, 1H)940

¹H-NMR(CDCl₃) δ ppm: 1.23(t, J=6Hz, 3H), 2.68(q, J=6Hz, 2H), 3.42(s,3H), 4.20 (s, 2H), 5.18(s, 2H), 6.78(d, J=8Hz, 1H), 6.82(d, J=8Hz, 1H),7.09(s, 1H), 7.16(d, J=8Hz, 1H), 7.22(d, J=8Hz, 1H), 7.78(s, 2H),7.82(s, 1H), 7.95(s, 1H)

Examples

The following compounds were obtained by treating the compounds in theabove table by the same method as the one of Example 9.

Ex. Structural formula MS M.p. NMR 941

ESI (+) 398 (MH⁺) 162- 164° C. ¹H-NMR(CDCl₃) δ ppm: 4.02(s, 2H), 4.18(d,J=5Hz, 2H, 6.75(d, J=8Hz, 1H), 6.86(d, J=8Hz, 1H), 6.89(s, 1H), 6.90(d,J=8Hz, 1H), 7.08(s, 1H), 7.10-7.40(m, 7H), 7.56(s, 1H), 7.69(s, 1H),7.96(s, 1H) 942

¹H-NMR(CDCl₃) δ ppm: 2.95(br.s, 4H), 4.13(s, 2H), 4.28(br.s, 1H),6.46(s, 1H), 6.73(d, J=8Hz, 1H), 6.78(s, 1H), 6.70- 6.80(m, 2H), 6.83(d,J=8Hz, 1H), 7.12-7.21(m, 3H), 7.23(m, 2H), 7.37(s, 1H), 7.58(s, 1H),7.73(s, 1H) 943

ESI (+) 336 (MH⁺) 202- 204° C. ¹H-NMR(CDCl₃) δ ppm: 1.10(t,J=6Hz, 3H),2.54(q, J=6Hz, 2H), 4.06(d, J=3Hz, 2H), 6.23(t, J=3Hz, 1H), 6.72(s, 1H),6.73(d, J=8hz, 1H), 6.76(br.s, 1H), 6.83(d, J=8Hz, 1H), 6.88(br.s, 1H),7.62(s, 2H), 7.80(br.s, 1H), 9.50(s, 1H)

Examples

The following compounds were obtained by treating(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbaldehydewith various amines by the same method as the one of Example 900 andthen treating the obtained products by the same method as the one ofExample 9.

Ex. Amine Structural formula MS M.p. NMR 944

160-164° C. ¹H-NMR(CDCl₃) δ ppm: 1.15(s, 6H), 1.21(t, J=6Hz, 3H), 1.20-1.30(m, 2H), 1.45- 1.55(m, 2H), 1.60- 1.70(m, 2H), 2.60- 2.75(m, 2H),3.62(s, 2H), 4.08(q, J=6Hz, 2H), 4.20 (br.s, 1H), 6.54(br.s, 1H),6.80(d, J=8Hz, 1H), 6.81(d, J=7Hz, 1H), 6.83(d, J=8Hz, 1H), 6.83(s, 1H),6.95(d, J=7Hz, 1H), 7.55(s, 1H), 7.70(d, J=3Hz, 2H) 945

ESI (+) 449 (MH⁺) ¹H-NMR(CD₃OD) δ ppm: 1.05(s, 6H), 1.25- 1.35(m, 2H),1.40- 1.50(m, 2H), 1.50- 1.62(m, 2H), 2.50- 2.65(m, 2H), 4.13(s, 2H),4.10(br.s, 2H), 4.25(br.s, 1H), 6.65(d, J=8Hz, 1H), 6.75(s, 1H), 6.76(d,J=8Hz, 1H), 6.89(d, J=7Hz, 1H), 6.95(d, J=7Hz, 1H), 7.50(s, 2H), 7.67(s,1H), 9.50(s, 1H)

Example 946 Ethyl5-[5-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl-methylamino)pyridin-2-yl]pentanoate

The title compound was obtained by treating(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbaldehydewith ethyl 5-(5-aminopyridin-2-yl)pentanoate by the same method as theone of Example 900 and then treating the obtained product by the samemethod as the one of Example 9.

1.23(t, J=6 Hz, 3H), 1.58-1.72(m, 4H), 2.30(t, J=6 Hz, 2H), 2.67(t, J=6Hz, 2H), 4.09(q, J=6 Hz, 2H), 4.14(s, 2H), 4.24(br.s, 1H), 6.48(s, 1H),6.73(d, J=8 Hz, 1H), 6.74(d, J=7 Hz, 1H), 6.90(d, J=8 Hz, 1H), 7.40(s,1H), 7.46(br.s, 1H), 7.59(s, 1H), 7.78(d, J=7 Hz, 1H), 7.90(m, 1H)

Example 9472-[5-(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)methylamino]pyridin-2-yl]ethanoland8-[N-(2-methylpyridin-5-yl)aminomethyl]-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]-benzothiazine

By the same method as the one of Example 900,(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbaldehyde was treated with 290 mg of a mixture of2-methyl-5-aminopyridine with ethyl(5-aminopyridin-2-yl)acetate and thenthe obtained product was reduced with sodium borohydride by heatingunder reflux to thereby give 230 mg of2-[5-[(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)methylamino]pyridin-2-yl]ethanoland 173 mg of8-[N-(2-methylpyridin-5-yl)aminomethyl]-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazineeach as a yellow oily substance.

2-[5-[(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)methylamino]pyridin-2-yl]ethanol

¹H-NMR(CDCl₃) δ ppm: 2.85(t, J=6 Hz, 2H), 3.45(br.s, 1H), 3.42(s, 3H),3.92(t, J=6 Hz, 2H), 4.20(s, 2H), 4.35(br.s, 1H), 5.20(s, 2H), 6.80(dd,J=2, 5 Hz, 1H), 6.85-6.98(m, 3H), 7.07(s, 1H), 7.80(s, 2H), 7.90(d, J=2Hz, 1H)

8-[N-(2-methylpyridin-5-yl)aminomethyl]-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine

¹H-NMR(CDCl₃) δ ppm: 2.37(s, 3H), 3.41(s, 3H), 4.21(s, 2H), 4.25(br.s,1H), 5.17(s, 2H), 6.73(dd, J=2, 5 Hz, 1H), 6.88(d, J=5 Hz, 1H), 6.90(s,2H), 7.08(s, 1H), 7.78(s, 2H), 7.92(d, J=2 Hz, 1H)

Examples

The following compounds were obtained by treating(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbaldehydewith aminopyridines by the same method as the one of Example 947.

Ex. Amine Structural formula NMR 948

¹H-NMR(CDCl₃) δ ppm: 1.70(br.s, 1H), 3.18(t, J=6Hz, 2H), 3.45(s, 3H),3.90(t, J=6Hz, 2H), 4.25(s, 2H), 5.22(s, 2H), 5.57(br.s, 1H), 6.80(dd,J=2, 5Hz, 1H), 6.92(d, J=8Hz, 1H), 6.97(d, J=8Hz, 1H), 7.10(d, J=5Hz,1H), 7.13(s, 1H), 7.22(s, 1H), 7.82(d, J=3Hz, 1H), 7.84(d, J=3Hz, 1H)949

¹H-NMR(CDCl₃) δ ppm: 1.30-1.48(m, 4H), 1.49- 1.60(m, 2H), 1.60-1.80(m,2H), 3.43(s, 3H), 3.58(t, J=6Hz, 2H), 4.13(t, J=6Hz, 2H), 4.18(s, 2H),4.19(s, 2H), 5.18(s, 2H), 6.57(d, J=8hz, 1H), 6.91(s, 2H), 6.92(d,J=8Hz, 1H), 7.08(s, 1H), 7.50(d, J=2Hz, 1H), 7.78(s, 2H)

Examples

The following compounds were obtained by treating(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbaldehydewith various aminopyridines by the same method as the one of Example900.

Ex Amine Structural formula NMR 950

¹H-NMR(CDCl₃) δ ppm: 1.23(t, J=6Hz, 3H), 3.42(s, 3H), 3.70(s, 2H),4.13(q, J=6Hz, 2H), 4.23(s, 2H), 4.30(br.s, 1H), 5.20(s, 2H), 6.82(dd,J=2, 5Hz, 1H), 6.92(d, J=8Hz, 1H), 6.95(d, J=8Hz, 1H), 7.05(d, J=5Hz,1H), 7.08(s, 1H), 7.79(d, J=3Hz, 1H), 7.81(d, J=3Hz, 1H), 7.98(d, J=2Hz,1H) 951

¹H-NMR(CDCl₃) δ ppm: 1.22(t, J=6Hz, 3H), 3.42(s, 3H), 3.82(s, 2H),4.22(s, 2H), 4.10(q, J=6Hz, 2H), 4.25(br.s, 1H), 5.18(s, 2H), 6.75(dd,J=2, 5Hz, 1H), 6.90(d, J=8Hz, 1H), 6.92(d, J=8Hz, 1H), 7.06(d, J=5Hz,1H), 7.07(s, 1H), 7.80(d, J=3Hz, 1H), 7.82(d, J=3Hz, 1H), 7.88(d, J=2Hz,1H) 952

¹H-NMR(CDCl₃) δ ppm: 1.22(t, J=6Hz, 3H), 1.38-1.50(m, 2H), 1.60- 1.70(m,2H), 1.70- 1.80(m, 2H), 2.28(t, J=6Hz, 2H), 3.42(s, 3H), 4.10(q, J=6Hz,2H), 4.20(s, 2H), 4.13(t, J=6Hz, 2H), 5.20(s, 2H), 6.57(d, J=8Hz, 1H),6.90(s, 2H), 6.92(d, J=8Hz, 1H), 7.08(s, 1H), 7.52(d, J=2Hz, 1H),7.80(s, 2H)

Examples

The following compounds were obtained by treating the compounds obtainedin Examples 947, 950, 952, 949, 951 and 948 by the same method as theone of Example 9.

Ex. Structural formula MS M.p. NMR 953

ESI (+) 352 (MH⁺) 138- 142° C. ¹H-NMR(CDCl₃) δ ppm: 2.86(t, J=5Hz, 2H),3.92(t, J=5Hz, 2H), 4.18(s, 2H), 4.20(br.s, 1H), 6.52(s, 1H), 6.78(d,J=8Hz, 1H), 6.80-6.86(m, 2H), 6.96(s, 1H), 6.97(d, J=8Hz, 1H), 6.82(s,1H), 7.52(d, J=2Hz, 1H), 7.63(d, J=2Hz, 1H), 7.90(d, J=2Hz, 1H) 954

ESI (+) 322 (MH⁺) 205- 208° C. ¹H-NMR(CDCl₃) δ ppm: 2.42(s. 3H),3.97(br.s, 1H), 3.98(t, J=5Hz, 1H), 4.18(d, J=5Hz, 1H), 6.48(br.s, 1H),6.52(s, 1H), 6.75-7.82(m, 2H), 6.86(d, J=8Hz, 1H), 6.92(d, J=8Hz, 1H),7.54(d, J=3Hz, 1H), 7.68(d, J=3Hz, 1H), 7.94(d, J=3Hz, 1H) 955

ESI (+) 394 (MH⁺) amor- phous ¹H-NMR(CDCl₃) δ ppm: 1.12(t, J=6Hz, 3H),3.69(s, 2H), 4.10(q, J=6Hz, 2H), 4.13(s, 2H), 4.30(br.s, 1H), 6.46(s,1H), 6.72(d, J=8Hz, 1H), 6.76(s, 1H), 6.78(d, J=8Hz, 1H), 7.03(d, J=7Hz,1H), 7.42(d, J=7Hz, 1H), 7.43(d, J=3Hz, 1H), 760(d, J=3Hz, 1H), 7.90(s,1H) 956

ESI (+) 466 (MH⁺) 105- 108° C. ¹H-NMR(CDCl₃) δ ppm: 1.23(t, J=6Hz, 3H),1.40- 1.50(m, 2H), 1.60-7.70(m, 2H), 1.70-1.80(m, 2H), 2.30(t, J=6Hz,2H), 4.10(br.s, 1H), 4.13(q J=6Hz, 2H), 4.15(q, J=6Hz, 2H), 4.18(s, 2H),6.57(br.s, 1H), 6.60(d, J=8Hz, 1H), 6.65-6.70(m, 1H), 6.81(s, 1H),6.82(s, 1H), 7.00(d, J=7Hz, 1H), 7.52(s, 1H), 7.58(br.s, 1H), 7.68(s,1H) 957

ESI (+) 424 (MH⁺) 124- 128° C. ¹H-NMR(CDCl₃) δ ppm: 1.16(br.s, 1H),1.30- 1.42(m, 4H), 1.42-1.60(m, 2H), 1.60-1.75(m, 2H), 3.58(t, J=6Hz,2H), 4.10(t, J=6Hz, 2H), 4.12(s, 2H), 4.10(br.s, 1H), 6.45(s, 1H),6.54(d, J=7Hz, 1H), 6.66(br.s, 1H), 6.72(d, J=7Hz, 1H), 6.78(d, J=8Hz,1H), 6.85(d, J=8Hz, 1H), 7.48(d, J=3Hz, 2H), 7.60(s, 1H) 958

ESI (+) 426 (MH⁺) 118- 122° C. ¹H-NMR(CDCl₃) δ ppm: 1.24(t, J=6Hz, 3H),3.85(s, 2H), 4.19(q J=6Hz, 2H), 4.21(s, 2H), 6.47(d, J=8Hz, 1H), 6.49(s,1H), 6.76-6.82(m, 1H), 6.80(br.s, 1H), 6.80(d, J=8Hz, 1H), 6.85(d,J=6Hz, 1H), 7.09(d, J=6Hz, 1H), 7.58(d, J=3Hz, 1H), 7.71(dd, J=2, 6Hz,1H), 7.90(s, 1H) 959

ESI (+) 384 (MH⁺) 138- 142° C. ¹H-NMR(CDCl₃) δ ppm: 1.60(br.s, 1H),3.19(t, J=6Hz, 2H), 3.93(t, J=6Hz, 2H), 4.19(s, 2H), 6.48(s, 1H),6.50(s, 1H), 6.80(br.s, 1H), 6.80(d, J=8Hz, 2H), 6.86(d, J=8hz, 1H),7.15(d, J=8Hz, 1H), 7.57(s, 1H), 7.70(s, 1H), 7.83(s, 1H)

Example 960[5-[(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)amino]pyridin-2-yloxy]aceticacid

The title compound was obtained by treatingethyl[5-[(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)amino]pyridin-2-yloxy]acetatesuccessively by the same methods as those of Examples 18 and 9.

¹H-NMR(DMSO-d₆) δ ppm: 4.14(s, 2H), 4.80(s, 2H), 6.49(br.s, 1H), 6.52(s,1H), 6.75(d, J=8 Hz, 1H), 6.78(s, 1H), 6.80(d, J=8 Hz, 1H), 6.84(d, J=7Hz, 1H), 7.12(d, J=7 Hz, 1H), 7.43(d, J=3 Hz, 1H), 7.56(d, J=3 Hz, 1H),7.62((d, J=3 Hz, 1H), 9.50(br.s, 1H)

MS: FAB(+)382(MH⁺)

m.p.: 170° C.

Examples

The following compounds were obtained by successively treating by thesame methods as those of Examples 18 and 9.

Ex. Structural formula MS M.p. NMR 961

ESI (+) 352 (MH⁺) 215- 220° C. ¹H-NMR(DMSO-d₆) δ ppm: 4.20(br.s, 1H),3.35(d, J=5Hz, 2H), 6.50(d, J=8Hz, 1H), 6.70-6.72(m, 1H), 6.70(d, J=8Hz,1H), 6.73(s, 1H), 6.82(d, J=8Hz, 1H), 7.62(s, 2H), 7.80(d, J=8Hz, 1H),9.50(br.s, 1H) 962

ESI (+) 398 (MH⁺) 114- 116° C. ¹H-NMR(DMSO-d₆) δ ppm: 3.78(s, 2H),4.10(s, 2H), 6.72(s, 1H), 6.75(d, J=8Hz, 1H), 6.85(d, J=8Hz, 1H),6.90(br.s, 1H), 6.95(dd, J=2, 7Hz, 1H), 7.12(d, J=7Hz, 1H), 7.60(s,2H),7;80(d, J=2Hz, 1H), 9.50(s, 1H) 963

¹H-NMR(DMSO-d6) δ ppm: 3.50(s, 2H), 4.05(d, J=5Hz, 2H), 6.42(t, J=5Hz,1H), 6.70-6.84(m, 2H), 6.78(s, 1H), 6.84(d, J=8Hz, 1H), 6.99(d, J=8Hz,1H), 7.62(s, 2H), 7.82(d, J=3Hz, 1H), 9.54(br.s, 1H) 964

ESI (+) 438 (MH⁺) ¹H-NMR(DMSO-d₆) δ ppm: 1.20-1.23(m, 2H), 1.40- 1.55(m,2H), 1.55-1.70(m, 2H), 2.18(t, J=6Hz, 2H), 3.97(br.s, 1H), 3.98(t,J=6Hz, 2H), 4.08(s, 2H), 6.60(d, J=8Hz, 1H), 6.75(s, 1H), 6.76(d, J=7Hz,1H), 6.81(d, J=8Hz, 1H), 7.05(d, J=7Hz, 1H), 7.40(s, 1H), 7.60(s, 2H),9.50(s, 1H) 965

¹H-NMR(DMSO-d₆) δ ppm: 1.40-1.50(m, 2H), 1.50- 1.60(m, 2H), 2.18(t,J=6Hz, 2H), 2.50(m, 2H), 4.08(d, J=5Hz, 2H), 6.28(t, J=5Hz, 1H), 6.68(m,3H), 6.80(d, J=8Hz, 1H), 6.83(d, J=8Hz, 1H), 7.60(s, 2H), 7.81(s, 1H),9.50(s, 1H) 966

ESI (+) 450 (MH⁺) 158- 161° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.02(s, 6H),1.10-1.20(m, 2H), 1.40-1.48(m, 2H), 1.48- 1.55(m, 2H), 2.40-2.50(m, 2H),4.08(d, J=5Hz, 1H), 6.23(t, J=5Hz, 1H), 6.70- 6.80(m, 1H), 6.72(s, 1H),6.73(d, J=8Hz, 1H), 6.74(d, J=7Hz, 1H), 6.85(d, J=8Hz, 1H), 6.89(d,J=7Hz, 1H), 7.60(s, 2H), 7.80(s, 1H), 9.50(s, 1H)

Example 9678-[(2-Methylquinolin-4-yl)aminomethyl]-[(10H-pyrazino[2,3-b][1,4]benzothiazine

Similar to Example 1094, 307 mg of8-chloromethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazinewas treated with 354 mg of 2-methyl-4-aminoquinoline in the presence of91 mg of sodium hydride (60% oily) to thereby give 413 mg of8-[(2-methylquinolin-4-yl)aminomethyl]-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazineas a yellow oily substance. Then this product was deblocked by the samemethod as the one of Example 9 to thereby give 114 mg of the titlecompound as, yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 3.53(s, 3H), 4.22(s, 2H), 6.74(d, J=8 Hz, 1H),6.79(s, 1H), 6.82(d, J=8 Hz, 1H), 6.82(s, 1H), 7.50(t, J=7 Hz, 1H),7.60(s, 2H), 7.64(t, J=7 Hz, 1H), 7.84(d, J=7 Hz, 1H), 8.14(d, J=7 Hz,1H), 9.48(br.s, 2H)

MS: ESI(+)372(MH⁺)

m.p.: 290-300° C.

Examples

The following compounds were synthesized by treating8-chloromethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]-benzothiazinewith amines by the same method as the one of Example 967 and thentreating by the same method as the one of Example 9.

Ex. Amino Structural formula MS M.p. NMR 968

ESI (+) 342 (MH⁺) 200- 203° C. ¹H-NMR(CDCl₃) δ ppm: 4.30(d, J=5Hz, 2H),6.50(d, J=8Hz, 1H), 6.70(d, J=8Hz, 1H), 6.72(s, 1H), 6.82(d, J=8Hz, 1H),7.25(t, J=5Hz, 1H), 7.42(d, J=8Hz, 1H), 7.61(s, 2H), 7.92(s, 1H),9.50(br.s, 1H) 969

FAB (+) 386 (MH⁺), 388 (MH⁺) 265- 268° C. ¹H-NMR(DMSC-d₆) δ ppm: 4.52(d,J=5Hz, 2H), 6.51(d, J=8Hz, 1H), 6.72(d, J=8Hz, 1H), 6.73(s, 1H), 6.85(d,J=8Hz, 1H), 7.00(t, J=5Hz, 1H), 7.45(d, J=8Hz, 1H), 7.62(s, 2H), 7.92(s,1H), 9.50(br.s, 1H)

Examples

Similar to Example 10947,N-[1-(2-trimethylsilylethoxy-methyl)imidazol-2-ylmethyl]acetamide and1-(2-trimethylsilylethoxymethyl)-2-(N-tert-butoxycarbonylaminomethyl)imidazolewere treated with8-chloromethyl-10-methoxy-10H-pyrazino[2,3-b][1,4]benzothiazine in thepresence of sodium hydride to thereby give the following compounds.

Amino- Ex. pyridine Structural formula NMR 970

¹H-NMR(CDCl₃) δ ppm: 0.02(s, 9H), 0.93(t, J=9Hz, 2H), 2.16(s, 3H),3.44(t, J=9Hz, 2H), 3.46(s, 3H), 4.64(s. 2H), 4.73(s, 2H), 5.29(s, 2H),5.44(s, 2H), 6.83(d, J=8Hz, 1H) 7.01-7.05(m, 4H), 7.88-7.90(m, 2H) 971

¹H-NMR(CDCl₃) δ ppm: 0.00(s, 9H), 0.92(m, 2H), 1.52(s, 9H), 3.49(m, 2H),3.57(s, 3H), 4.41(s, 2H), 4.62(br.s, 2H), 5.31(s, 2H), 5.39(s, 2H),6.90(d, J=8Hz, 1H), 6.97-7.12 (m, 4H), 7.86(m, 2H)

Examples

The following compounds were obtained by treating the compounds obtainedin Examples 970 and 971 by the same method as the one of Example 9.

Ex. Structural formula MS M.p. NMR 972

FAB (+) 353 (MH⁺) ¹H-NMR(CDCl₃) δ ppm: 2.10(s, 3H), 4.39(s, 2H), 4.43(s,2H), 6.25(s, 1H), 6.57(d, J=8Hz, 1H), 6.79(d, J=8Hz, 1H), 6.92(s, 3H),7.41(d, J=3Hz, 1H), 7.63(d, J=3Hz, 1H) 973

¹H-NMR(DMSO-d₆) δ ppm: 3.52(s, 2H), 3.66(s, 2H), 6.74(d, J=1Hz, 1H),6.78(d, J=1Hz, 1H), 6.85(d, J=8Hz, 1H), 6.91(s, 2H), 7.62(d, J=3Hz, 1H),7.63(d, J=3Hz, 1H), 9.47(s, 1H)

Example 974N-(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-N-(pyridin-3-yl)acetamide

The title compound was obtained by treating10-methoxymethyl-8-[N-(pyridin-3-yl)aminomethyl]-10H-pyrazino[2,3-b][1,4]-benzothiazineby the same method as the one of Production Example 85.

¹H-NMR(CDCl₃) δ ppm: 1.90(s, 3H), 3.42(s, 3H), 4.80(s, 2H), 5.19(s, 2H),6.78(d, J=8 Hz, 1H), 6.92(d, J=8 Hz, 1H), 6.97(s, 1H), 7.30-7.42(m, 2H),7.83(d, J=3 Hz, 2H), 8.38(br.s, 1H), 8.58(br.s, 1H)

Example 975N-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-N-(3-pyridyl)acetamide

The title compound was obtained by treatingN-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-N-(pyridin-3-yl)acetamideby the same method as the one of Example 9.

¹H-NMR(DMSO-d₆) δ ppm: 1.82(s, 3H), 4.88(s, 2H), 6.58(d, J=8 Hz, 1H),6.63(s, 1H), 6.80(d, J=8 Hz, 1H), 7.45(br.s, 1H), 7.60(s, 2H),7.68-7.70(m, 1H), 8.43-8.50(m, 2H), 9.41(s, 1H)

MS: ESI(+)350(MH⁺)

m.p.: 212-214° C.

Example 976N-(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-N-(pyridin-3-yl)-N′-ethylurea

341 mg of10-methoxymethyl-8-[N-(pyridin-3-yl)aminomethyl]-10H-pyrazino[2,3-b][1,4]benzothiazinewas dissolved in 5 ml of toluene. After adding 3 ml of pyridine and 1.9ml of ethyl isocyanate, the reaction mixture was heated under reflux for3 days. After the completion of the reaction, the reaction mixture waspoured into a saturated aqueous solution of sodium chloride andextracted repeatedly with ethyl acetate. After distilling off thesolvent under reduced pressure, the residue was purified by silica gelcolumn chromatography (eluted with toluene/acetone) to thereby give 350mg of the title compound as a yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.03(t, J=6 Hz, 3H), 3.17(q, J=6 Hz, 2H), 3.42(s,3H), 4.29(br.s, 1H), 4.75(s, 2H), 5.14(s, 2H), 6.80(d, J=8 Hz, 1H),6.86(d, J=8 Hz, 1H), 6.97(s, 1H), 7.18-7.23(m, 1H), 7.23(d, J=5 Hz, 1H),7.42(d, J=5 Hz, 1H), 7.77(s, 2H), 8.40(s, 1H)

Example 977N-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-N-(pyridin-3-yl)-N′-ethylurea

The title compound was obtained by treatingN-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-N-(pyridin-3-yl)-N′-ethylureaby the same method as the one of Example 9.

¹H-NMR(DMSO-d₆) δ ppm: 0.96(t, J=6 Hz, 3H), 3.06(q, J=6 Hz, 2H), 4.68(s,2H), 6.26(t, J=7 Hz, 1H), 6.58(d, J=8 Hz, 1H), 6.69(s, 1H), 6.79(d, J=8Hz, 1H), 7.30-7.40(m, 1H), 7.53-7.62(m, 1H), 7.60(s, 2H), 8.16(m, 1H),8.20(m, 1H), 9.48(s, 1H)

MS: ESI(+)379(MH⁺)

m.p.: 210-212° C.

Examples

The following compounds were obtained by treating10-methoxymethyl-8-[N-(pyridin-3-yl)aminomethyl]-10H-pyrazino[2,3-b][1,4]benzothiazineby the same method as the one of Example 974 or 976 followed by the sametreatment as the one of Example 9.

Ex. Structural formula MS M.p. NMR 978

ESI (+) 448 (MH⁺) 205-260° C. ¹H-NMR(DMSO-d₆) δ ppm: 4.68(s, 2H),6.60(d, J=8Hz, 1H), 6.77(d, J=8Hz, 1H), 6.79(s, 1H), 7.32(dd, J=2, 5Hz,1H), 7.47-7.56(m, 1H), 7.58-7.62(m, 6H), 7.70- 7.76(m, 1H), 8.30(d,J=3Hz, 1H), 8.42(d, J=3Hz, 1H), 9.50(br.s, 1H) 979

FAB (+) 411 (M⁺) 178-182° C. ¹H-NMR(CDCl₃) δ ppm: 4.92(s, 2H), 6.60(d,J=8Hz, 1H), 6.61(s, 1H), 6.72(d, J=8Hz, 1H), 7.05-7.20(m, 3H),7.20-7.40(m, 5H), 7.53(d, J=3Hz, 1H), 7.60(d, J=3Hz, 1H), 8.24(s, 1H),8.36(d, J=2Hz, 1H) 980

FAB (+) 385 (M⁺) 208-210° C. ¹H-NMR(DMSO-d₆) δ ppm: 3.14(s, 3H), 4.73(s,2H), 6.62(d, J=8Hz, 1H), 6.73(s, 1H), 6.78(d, J=8Hz, 1H), 7.40(m, 1H),7.60(m, 2H), 7.84(dd, J=2, 8Hz, 1H), 8.43(d, J=4Hz, 1H), 8.54(s, 1H),9.50(s, 1H) 981

ESI (+) 427 (MH⁺) 208-210° C. ¹H-NMR(DMSO-d₆) δ ppm: 4.78(s, 2H),6.65(d, J=8Hz, 1H), 6.77(s, 1H), 6.81(d, J=8Hz, 1H), 6.95(t, J=7Hz, 2H),7.22(t, J=7Hz, 2H), 7.22(t, J=7Hz, 2H), 7.42(d, J=7Hz, 2H), 7.60(d,J=2Hz, 1H), 7.61(d, J=2Hz, 1H), 7.69(m, 1H), # 8.38(d, J=2Hz, 1H),8.42(s, 1H), 8.48(s, 1H), 9.52(s, 1H)

Examples

The following compounds were obtained by treating10-methoxymethyl-8-chloromethyl-10H-pyrazino([2,3-b][1,4]-benzothiazinewith various imidazoles by the same method as the one of Example 1094.

Ex. Imidazole Structural formula NMR 982

¹H-NMR(CDCl₃) δ ppm: 2.34(s, 3H), 3.45(s, 3H), 4.98(s, 2H), 5.16(s, 2H),6.64(dd, J=1, 8Hz, 1H), 6.77(d, J=1Hz, 1H), 6.84(d, J=1Hz, 1H), 6.96(d,J=1Hz, 1H), 6.97(d, J=8Hz, 1H), 7.84(d, J=3Hz, 1H), 7.85(d, J=3Hz, 1H)983

¹H-NMR(CDCl₃) δ ppm: 1.27(t, J=7Hz, 3H), 2.61(q, J=7Hz, 2H), 3.42(s,2H), 4.98(s, 2H), 5.12(s, 2H), 6.61(d, J=8Hz, 1H), 6.71(s, 1H), 6.82(s,1H), 6.94(d, J=8Hz, 1H), 6.98(s, 1H), 7.82(m, 2H) 984

¹H-NMR(CDCl₃) δ ppm: 1.27(d, J=7Hz, 6H), 2.93(sept, J=7Hz, 1H), 3.42(s,3H), 5.03(s, 2H), 5.13(s, 2H), 6.63(d, J=8Hz, 1H), 6.70(s, 1H), 6.78(s,1H), 6.96(d, J=8Hz, 1H), 7.02(s, 1H), 7.83(m, 2H) 985

¹H-NMR(CDCl₃) δ ppm: 3.48(s, 3H), 5.03(s, 2H), 5.19(s, 2H), 6.73(dd,J=2, 8Hz, 1H), 6.89(d, J=2Hz, 1H), 6.91(d, J=1Hz, 1H), 6.99(d, J=1Hz,1H), 7.00(d, J=8Hz, 1H), 7.84(d, J=3Hz, 1H), 7.86(d, J=3Hz, 1H) 986

¹H-NMR(CDCl₃) δ ppm: 3.47(s, 3H), 5.05(s, 2H), 5.19(s, 2H), 6.74(dd,J=2, 8Hz, 1H), 6.89(d, J=2Hz, 1H), 6.97(d, J=1Hz, 1H), 6.99(d, J=8Hz,1H), 7.06(d, J=1Hz, 1H), 7.84(d, J=3Hz, 1H), 7.86(d, J=3Hz, 1H) 987

¹H-NMR(CDCl₃) δ ppm: 3.46(s, 3H), 5.17(s, 2H), 5.18(s, 2H), 6.75(dd,J=1, 8Hz, 1H), 6.88(br.s, 1H), 6.98(s, 1H), 7.00(d, J=8Hz, 1H), 7.13(s,1H), 7.83- 7.88(m, 2H) 988

¹H-NMR(CDCl₃) δ ppm: 3.46(s, 3H), 4.86(s, 2H), 5.19(s, 2H), 6.59(d,J=2Hz, 1H), 6.70(d, J=2Hz, 1H), 6.72(d, J=2Hz, 1H), 6.87(d, J=2Hz, 1H),7.00(d, J=8Hz, 1H), 7.84(d, J=3Hz, 1H), 7.86(d, J=3Hz, 1H) 989

¹H-NMR(CDCl₃) δ ppm: 3.48(s, 3H), 5.19(s, 2H), 5.53(s, 2H), 6.78(d,J=8Hz, 1H), 6.97(s, 2H), 7.17(s, 1H), 7.28(s, 1H), 7.83(m, 2H), 9.84(s,1H) 990

¹H-NMR(CDCl₃) δ ppm: 3.48(s, 3H), 5.20(s, 2H), 5.64(s, 2H), 6.87(dd,J=2, 8Hz, 1H), 6.99(d, J=8Hz, 1H), 7.05(d, J=2Hz, 1H), 7.20(d, J=1Hz,1H), 7.33(d, J=1Hz, 1H), 7.47(ddd, J=2, 5, 8Hz, 1H), 7.83-7.88(m, 3H),8.26(dd, J=2, 8Hz, 1H), 8.81(dd, J=1, 5Hz, 1H) 991

¹H-NMR(CDCl₃) δ ppm: 3.42(s, 3H), 4.24(s, 2H), 5.08(s, 2H), 5.12(s, 2H),6.54(dd, J=2, 8Hz, 1H), 6.69(d, J=2Hz, 1H), 6.85(d, J=1Hz, 1H), 6.88(d,J=8Hz, 1H), 7.03(d, J=1Hz, 1H), 7.07(ddd, J=2, 5, 8Hz, 1H), 7.19(br.d,J=8Hz, 1H), 7.54(dt, J=2, 8Hz, 1H), 7.83(d, # J=3Hz, 1H), 7.84(d, J=3Hz,1H), 8.42(ddd, J=1, 2, 5Hz, 1H) 992

¹H-NMR(CDCl₃) δ ppm: 3.43(s, 3H), 5.08(s, 2H), 5.19(s, 2H), 6.79(dd,J=2, 8Hz, 1H), 6.92(d, J=2Hz, 1H), 7.00(d, J=8Hz, 1H), 7.19(d, J=2Hz,1H), 7.23(t, J=8Hz, 1H), 7.36(t, J=8Hz, 2H), 7.60(d, J=2Hz, 1H), 7.75(d,J=8Hz, 2H), 7.83(d, J=3Hz, 1H), 7.85(d, J=3Hz, 1H), 993

¹H-NMR(CDCl₃) δ ppm: 3.43(s, 3H), 5.10(s, 2H), 5.20(s, 2H), 6.80(dd,J=2, 8Hz, 1H), 6.94(d, J=2Hz, 1H), 7.02(d, J=8Hz, 1H), 7.35(d, J=1Hz,1H), 7.62(dd, J=2, 5Hz, 2H), 7.64(t, J=1Hz, 1H), 7.84(d, J=3Hz, 1H),7.87(d, J=3Hz, 1H), 8.57(dd, J=2, 5Hz, 2H) 994

¹H-NMR(DMSO-d₆) δ ppm: 3.0-3.4(br.s, total 1H), 3.43 and 3.47(s, total3H, 3:4), 4.50 and 4.54(s, total 2H, 3:4), 5.00 and 5.16(s, total 2H,4:3), 5.16 and 5.20(s, total 2H, 4:3), 6.70 and 6.73(dd, J=1.8, 8.1Hz,total 1H, 3:4), 6.84 and 6.90(d, J=1.8Hz, total 1H, 3:4), # 6.85 and6.94(s, total 1H), 4:3), 6.95 and 6.97(d, J=8.1Hz, total 1H, 3:4),7.48(s, total 1H), 7.83 and 7.84(d, J=2.5Hz, total 1H, 3:4), 7.84 and7.85(d, J=8.1Hz, total 1H, 3:4) 995

¹H-NMR(CDCl₃) δ ppm: 3.52(s, 3H), 5.20(s, 2H), 5.26(s, 2H), 6.85(dd,J=2, 8Hz, 1H), 7.06(d, J=8Hz, 1H), 7.09(d, J=2Hz, 1H), 7.72(s, 1H),7.86(d, J=3Hz, 1H), 7.88(d, J=3Hz, 1H) 996

¹H-NMR(CDCl₃) δ ppm: 3.44(s, 3H), 5.09(s, 2H), 5.21(s, 2H), 6.79(dd,J=2, 8Hz, 1H), 6.94(d, J=2Hz, 1H), 7.01(d, J=8Hz, 1H), 7.29(d, J=1Hz,1H), 7.62- 7.65(m, 3H), 7.83-7.87(m, 4H) 997

¹H-NMR(CDCl₃) δ ppm: 2.30(s, 3H), 3.46(s, 3H), 5.01(s, 2H), 5.17(s, 2H),6.62-6.67(m, 1H), 6.77(d, J=2Hz, 1H), 7.01(d, J=8Hz, 1H), 7.48(s, 1H),7.84(d, J=3Hz, 1H), 7.87(d, J=3Hz, 1H) 998

¹H-NMR(CDCl₃) δ ppm: 2.68(t, J=8Hz, 2H), 3.25(q, J=8Hz, 2H), 3.46(s,3H), 4.96(s, 2H), 5.20(s, 2H), 5.86(br.s, 1H), 6.62(s, 1H), 6.73(d,J=8Hz, 1H), 6.88(s, 1H), 6.97(d, J=8Hz, 1H), 7.43(s, 1H), 7.48(t, J=8Hz,2H), 7.50-7.58(d, 1H), 7.80-7.90(m, 4H) 999

¹H-NMR(CDCl₃) δ ppm: 2.86(t, J=6Hz, 2H), 3.45(s, 3H), 3.68-3.76(m, 2H),5.00(s, 2H), 5.19(s, 2H), 6.73(s, 1H), 6.70- 6.76(m, 1H), 6.89(s, 1H),6.97(d, J=8Hz, 1H), 7.40(t, J=8Hz, 2H), 7.44- 7.49(m, 1H), 7.51(s, 1H),7.52-7.60(m, 1H), 7.80(d, J=8Hz, 2H), 7.80-7.88(m, 2H)

Examples

The following compounds were obtained by the same method as the one ofExample 8.

Ex. Structural formula MS M.p. NMR 1000

ESI(+) 296.2 (MH⁺) 244-246° C. ¹H-NMR(DMSO-d₆) δ ppm: 2.27(s, 3H),5.01(s, 2H), 6.53(s, 1H), 6.56(d, J=8Hz, 1H), 6.89(d, J=8Hz, 1H),6.93(s, 1H), 7.16(s, 1H), 7.63(s, 2H), 9.53(s, 1H) 1001

ESI(+) 310.2 (MH⁺) 230-231° C. ¹H-NMR(CDCl₃) δ ppm: 1.27(t, J=7Hz, 3H),2.61(q, J=7Hz, 2H), 4.90(s, 2H), 6.09(d, J=2Hz, 1H), 6.55(dd, J=2, 8Hz,1H), 6.79(br.s, 1H), 6.82(d, J=1Hz, 1H), 6.85(d, J=8Hz, 1H), 6.99(d,J=1Hz, 1H), 7.56(d, J=3Hz, 1H), 7.69(d, J=3Hz, 1H) 1002

ESI(+) 324.0 (MH⁺) 241-242° C. ¹H-NMR(CDCl₃) δ ppm: 1.26(d, J=7Hz, 6H),2.90(septet, J=7Hz, 1H), 4.94(s, 2H), 6.09(d, J=2Hz, 1H), 6.55(dd, J=2,8Hz, 1H), 6.76(d, J=1Hz, 1H), 6.85(d, J=8Hz, 1H), 6.98(d, J=1Hz, 1H),7.18(br.s, 1H), 7.52(d, J=3Hz, 1H), 7. # 68(d, J=3Hz, 1H) 1003

ESI (+) 465 (MH⁺) 127-130° C. ¹H-NMR(CDCl₃) δ ppm: 2.70(t, J=6Hz, 2H),3.27(q, J=6Hz, 2H), 4.88(s, 2H), 6.21(s, 1H), 6.64(s, 1H), 6.63(dd, J=2,8Hz, 1H), 6.86(d, J=8Hz, 1H), 7.40(s, 1H), 7.48(t, J=8Hz, 2H),7.52-7.58(m, 2H), 7.68(d, # J=3Hz, 1H), 7.85(d, J=8Hz, 2H) 1004

ESI (+) 429 (MH⁺) 231-233° C. ¹H-NMR(DMSO-d₆) δ ppm: 2.97(t, J=6Hz, 2H),3.62(q, J=6Hz, 2H), 5.29(s, 2H), 6.75(d, J=1Hz, 1H), 6.76(dd, J=1, 8Hz,1H), 6.91(d, J=8Hz, 1H), 7.47(t, J=7Hz, 2H), 7.53(t, J=7Hz, 1H), 7.55(s,1H), 7.72(s, 2H), 7.85(d, J=7Hz, # 2H), 8.78(t, J=6Hz, 1H), 9.27(s, 1H),9.66(s, 1H)

Examples

The following compounds were obtained by the same method as the one ofExample 9.

Ex. Structural formula MS M.p. NMR 1005

FAB (+) 316 (MH⁺) 231-232° C. ¹H-NMR(DMSO-d₆) δ ppm: 5.01(s, 2H),6.55(d, J=1Hz, 1H), 6.59(dd, J=1, 8Hz, 1H), 6.90(d, J=8Hz, 1H), 6.92(d,J=2Hz, 1H), 7.34(d, J=2Hz, 1H), 7.63(s, 2H), 9.55(s, 1H) 1006

FAB (+) 361 (M⁺) 256-258° C. ¹H-NMR(DMSO-d₆) δ ppm: 5.00(s, 2H), 6.54(s,1H), 6.56(d, J=8Hz, 1H), 6.90(d, J=8Hz, 1H), 6.97(d, J=2Hz, 1H), 7.39(d,J=2Hz, 1H), 7.63(s, 2H), 9.45(s, 1H) 1007

FAB (+) 350 (MH⁺) 231-233° C. ¹H-NMR(DMSO-d₆) δ ppm: 5.20(s, 2H),6.50(d, J=1Hz, 1H), 6.57(dd, J=1, 8Hz, 1H), 6.90(d, J=8Hz, 1H), 7.15(d,J=1Hz, 1H), 7.54(d, J=1Hz, 1H), 7.63(s, 2H), 9.55(s, 1H) 1008

FAB (+) 297 (MH⁺) 286-287° C. ¹H-NMR(DMSO-d₆) δ ppm: 4.87(s, 2H),6.56(s, 1H), 6.59(d, J=8Hz, 1H), 6.74(s, 1H), 6.77(s, 1H), 6.90(d,J=8Hz, 1H), 6.92(br.s, 2H), 7.63(s, 2H), 9.57(s, 1H) 1009

FAB (+) 387 (MH⁺) 191-193° C. ¹H-NMR(CDCl₃) δ ppm: 5.52(s, 2H), 6.43(s,1H), 6.72(d, J=8Hz, 1H), 6.84(d, J=8Hz, 1H), 6.95(s, 1H), 7.19(s, 1H),7.32(s, 1H), 7.47(dd, J=5, 8Hz, 1H), 7.53(d, J=3Hz, 1H), 7.65(d, J=3Hz,1H), 7.85(td, J=1, 8Hz, 1H), 8.15(d, J=8Hz, 1H), 8.78(d, J=5Hz, 1H) 1010

FAB (+) 373 (MH⁺) 216-219° C. ¹H-NMR(DMSO-d₆) δ ppm: 4.10(s, 2H),5.04(s, 2H), 6.45(d, J=8Hz, 1H), 6.48(s, 1H), 6.81(d, J=8Hz, 1H),6.82(s, 1H), 7.09(s, 1H), 7.14(d, J=9Hz, 1H), 7.16(dd, J=6, 9Hz, 1H),7.63(s, 2H), 7.64(dt, J=2, 9Hz, 1H), 8.41(dd, J=2, # 6Hz, 1H), 9.49(s,1H) 1011

FAB (+) 358 (MH⁺) 216-218° C. ¹H-NMR(DMSO-d₆) δ ppm: 5.05(s, 2H),6.62(d, J=1Hz, 1H), 6.68(dd, J=1, 8Hz, 1H), 6.90(d, J=8Hz, 1H), 7.16(t,J=8Hz, 1H), 7.31(t, J=8Hz, 2H), 7.59(s, 1H), 7.62(s, 2H), 7.73(d, J=8Hz,2H), 7.75(s, 1H), 9.53(s, 1H) 1012

FAB (+) 359 (MH⁺) 157-158° C. ¹H-NMR(DMSO-d₆) δ ppm: 5.17(s, 2H),6.63(d, J=1Hz, 1H), 6.73(dd, J=1, 7Hz, 1H), 6.94(d, J=7Hz, 1H), 7.64(s,2H), 8.20(d, J=1Hz, 1H), 8.24(d, J=6Hz, 2H), 8.38(s, J=1Hz, 1H), 8.75(d,J=6Hz, 2H), 9.54(s, 1H) 1013

FAB (+) 383 (M⁺) 262-264° C. ¹H-NMR(DMSO-d₆) δ ppm: 5.09(s, 2H), 6.60(d,J=1Hz, 1H), 6.69(dd, J=1, 8Hz, 1H), 6.91(d, J=8Hz, 1H), 7.62(s, 2H),7.77(d, J=8Hz, 2H), 7.85(d, J=1Hz, 1H), 7.86(d, J=1Hz, 1H), 7.91(d,J=8Hz, 2H), 9.52(s, 1H)

Examples

The following compounds were obtained by the same treatment as the oneof Example 434.

Ex. Structural formula MS M.p. NMR 1014

218-219° C. ¹H-NMR(DMSO-d₆) δ ppm: 5.41(s, 2H), 6.53(d, J=1Hz, 1H),6.57(dd, J=1, 9Hz, 1H), 6.86(d, J=9Hz, 1H), 7.33(s, 1H), 7.63(s, 2H),7.69(s, 1H), 9.49(s, 1H), 9.68(s, 1H) 1015

ESI (+) 312.0 (M⁺) 208-215° C. ¹H-NMR(DMSO-d₆) δ ppm: 4.38(m, 2H), 4.79and 5.08(t, J=6Hz, 1H), 4.79 and 5.06(s, 2H), 6.54-6.65(m, 2H), 6.85-6.90(m, 1H), 6.82 and 6.91(s, 1H), 7.59 and 7.63(s, 1H), 7.63- 7.65(m,2H), 9.51 and 9.53(s, 1H) 1016

¹H-NMR(DMSO-d₆) δ ppm: 5.34(s, 2H), 6.56(d, J=2Hz, 1H), 6.73(dd, J=2,8Hz, 1H), 6.96(d, J=8Hz, 1H), 7.66(s, 2H), 8.48(s, 1H), 9.54(s, 1H) 1017

¹H-NMR(DMSO-d₆) δ ppm: 2.24(s, 3H), 5.12(s, 2H), 6.47(d, J=2Hz, 1H),6.62(dd, J=2, 8Hz, 1H), 6.92(d, J=8Hz, 1H), 7.65(s, 2H), 7.90(s, 1H),9.50(s, 1H)

Examples

280 mg portions of the following compounds were obtained by the samemethod as the one of Example 1094 by starting with 0.55 g ofethyl(5-methylimidazol-4-yl)carboxylate and 0.7 g of10-methoxymethyl-8-chloromethyl-10H-pyrazino[2,3-b][1,4]benzothiazine.

Ex. Structural formula NMR 1018

¹H-NMR(CDCl₃) δ ppm: 1.40(t, J=7Hz, 3H), 2.47(s, 3H), 3.45(s, 3H),4.37(q, J=7Hz, 2H), 5.02(s, 2H), 5.17(s, 2H), 6.62(dd, J=2, 8Hz, 1H),6.80(d, J=2Hz, 1H), 6.98(d, J=8Hz, 1H), 7.48(s, 1H), 7.84(d, J=3Hz, 1H),7.86(d, J=3Hz, 1H) 1019

¹H-NMR(CDCl₃) δ ppm: 1.33(t, J=7Hz, 3H), 2.51(s, 3H), 3.46(s, 3H),4.28(q, J=7Hz, 2H), 5.18(s, 2H), 5.40(s, 2H), 6.73(dd, J=2, 8Hz, 1H),6.87(d, J=8Hz, 1H), 6.96(d, J=8Hz, 1H), 7.53(s, 1H), 7.83(d, J=3Hz, 1H),7.85(d, J=3Hz, 1H)

Examples

The following compounds were obtained by the same method as the one ofExample 1094 by starting with10-methoxymethyl-8-chloromethyl-10H-pyrazino[2,3-b][1,4]benzothiazineand various imidazoles.

Ex. Imidazole Structural formula NMR 1020

¹H-NMR(DMSO-d₆) δ ppm: 3.33(s, 3H), 3.65(s, 3H), 5.66(s, 2H), 5.70(s,2H), 6.33(d, J=15.5Hz, 1H), 6.88(dd, J=1.7, 8.3Hz, 1H), 6.97(d, J=1.7Hz,1H), 7.12(d, J=8.3Hz, 1H), 7.48(d, J=15.5Hz, 1H), 7.62(s, 1H), 7.86(s,1H), 7.93(d, J=3.0Hz, 1H), 7.96(d, J=3.0Hz, 1H) 1021

¹H-NMR(CDCl₃) δ ppm: 3.42(s, 3H), 3.81(s, 3H), 5.09(s, 2H), 5.20(s, 2H),6.80(dd, J=2, 8Hz, 1H), 6.93(d, J=2Hz, 1H), 7.01(d, J=8Hz, 1H), 7.29(d,J=1Hz, 1H), 7.63(d, J=1Hz, 1H), 7.82(d, J=8Hz, 2H), 7.83(d, J=3Hz, 1H),7.86(d, J=3Hz, 1H), 8.03(d, J=8Hz, 2H) 1022

¹H-NMR(CDCl₃) δ ppm: 3.43(s, 3H), 3.87(s, 3H), 4.08(s, 2H), 4.83(s, 2H),5.10(s, 2H), 6.63(s, 1H), 6.76(d, J=8Hz, 1H), 6.90(d, J=8Hz, 1H),6.99(s, 1H), 7.16(d, J=8Hz, 2H), 7.78(s, 1H), 7.87-7.93(m, 4H) 1023

¹H-NMR(CDCl₃) δ ppm: 3.43(s, 3H), 3.94(s, 3H), 5.18(s, 2H), 5.63(s, 2H),6.83(dd, J=2, 8Hz, 1H), 6.99(d, J=8Hz, 1H), 7.01(d, J=2Hz, 1H), 7.20(d,J=1Hz, 1H), 7.30(d, J=1Hz, 1H), 7.83(d, J=3Hz, 1H), 7.84(d, J=3Hz, 1H),8.13(d, J=8Hz, 2H), 8.30(d, J=8Hz, 2H)

Examples

The following compounds were obtained by treating the starting compoundsby the same method as the one of Example 434.

Ex. Structural formula MS M. p. NMR 1024

ESI (+) 368 (MH⁺) 222-224° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.25(q, J=7Hz,3H), 2.33(s, 3H), 4.19(q, J=7Hz, 2H), 5.09(s, 2H), 6.45(d, J=2Hz, 1H),6.56(dd, J=2, 8Hz, 1H), 6.89(d, J=8Hz, 1H), 7.62(s, 2H), 7.84(s, 1H),9.48(s, 1H) 1025

ESI (+) 368 (MH⁺) 194-196° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.23(t, J=7Hz,3H), 2.38(s, 3H), 4.18(q, J=7Hz, 2H), 5.30(s, 2H), 6.48(s, 1H),6.45-6.54(m, 1H), 6.86(d, J=8Hz, 1H), 7.64(s, 2H), 7.94(s, 1H), 9.52(s,1H) 1026

ESI (+) 366.1 (MH⁺) 248-250° C. ¹H-NMR (DMSO-d₆) δ ppm: 3.65(s, 3H),5.05(s, 2H), 6.33(d, J=15.6Hz, 1H), 6.56(s, 1H), 6.66(d, J=7.9Hz, 1H),6.90(d, J=7.9Hz, 1H), 7.49(d, J=15.6Hz, 1H), 7.56(s, 1H), 7.63(s, 2H),7.81(s, 1H), 9.52(s, 1H)

Example 1027 Methyl4-[1-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)imidazol-4-yl]benzoatetrifluoroacetate

The title compound was obtained by treating methyl4-[1-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)imidazol-4-yl]benzoateby the same method as the one of Example 9.

¹H-NMR(DMSO-d₆) δ ppm: 3.83(s, 3H), 5.19(s, 2H), 6.64(d, J=1 Hz, 1H),6.76(dd, J=1, 7 Hz, 1H), 6.95(d, J=7 Hz, 1H), 7.64(s, 2H), 7.90(d, J=8Hz, 2H), 8.00(d, J=8 Hz, 2H), 8.06(s, 1H), 8.75(s, 1H), 9.54(s, 1H)

MS: FAB(+)416(MH⁺)

m.p.: 161-162° C.

Example 1028(E)-3-[1-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)imidazol-4-yl]-2-propenoicacid

The title compound was obtained as yellow crystals by treatingmethyl(E)-3-[1-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)imidazol-4-yl]propenoatesuccessively by the same methods as those of Examples 434 and 18.

¹H-NMR(DMSO-d₆) δ ppm: 5.04(s, 2H), 6.26(d, J=15.4 Hz, 1H), 6.56(s, 1H),6.65(d, J=7.9 Hz, 1H), 6.90(d, J=7.9 Hz, 1H), 7.41(d, J=15.4 Hz, 1H),7.52(s, 1H), 7.63(s, 2H), 7.89(s, 1H), 9.52(s, 1H)

MS: ESI(+)352.2(MH⁺)

m.p.: 275-276° C.

Examples

The following compounds were obtained by treating the compounds obtainedin Examples 1021, 1022 and 1023 successively by the same methods asthose of Examples 9 and 18.

Ex. Structural formula MS M. p. NMR 1029

FAB (+) 402 (M⁺) 264-266° C. ¹H-NMR (DMSO-d₆) δ ppm: 5.20(s, 2H),6.64(d, J=1Hz, 1H), 6.77(dd, J=1, 7Hz, 1H), 6.94(d, J=7Hz, 1H), 7.64(s,2H), 7.86(d, J=8Hz, 2H), 7.97(d, J=8Hz, 2H), 8.18(s, 1H), 8.65(s, 1H),9.54(s, 1H) 1030

FAB (+) 416 (MH⁺) 185-188° C. ¹H-NMR (DMSO-d₆) δ ppm: 4.03(s, 2H),4.94(s, 2H), 6.42(s, 1H), 6.44(d, J=8Hz, 1H), 6.78(d, J=8Hz, 1H),6.85(s, 1H), 7.11(s, 1H), 7.20(d, J=8Hz, 2H), 7.63(s, 2H), 7.78(d,J=8Hz, 2H), 9.45(s, 1H), 13.50(br.s, 1H) 1031

FAB (+) 430 (MH⁺) 242-246° C. ¹H-NMR (DMSO-d₆) δ ppm: 5.53(s, 2H),6.55(d, J=1Hz, 1H), 6.62(dd, J=1, 8Hz, 1H), 6.87(d, J=8Hz, 1H), 7.33(s,1H), 7.62(s, 2H), 7.75(s, 1H), 8.04(d, J=8Hz, 2H), 8.25(d, J=8Hz, 2H),9.51(s, 1H)

Example 1032[1-[10-(Methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-5-methylimidazol-4-yl]carboxamide

To a solution of 0.7 g ofethyl[1-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-5-methylimidazol-4-yl]carboxylatein tetrahydrofuran (10 ml) was added 50 ml of aqueous ammonia. Aftersealing, the resulting mixture was heated to 100° C. for 24 hours.

Then the reaction mixture was concentrated, extracted withdichloromethane, washed with a saturated aqueous solution of sodiumchloride and dried over anhydrous magnesium sulfate. After distillingoff the solvent under reduced pressure, the residue was purified bysilica gel column chromatography (eluted with ethanol/dichloromethane)to thereby give 0.31 g of the title compound as pale yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 2.35(s, 3H), 3.29(s, 3H), 5.15(s, 4H), 6.73(dd,J=2, 8 Hz, 1H), 6.82(d, J=2 Hz, 1H), 6.92-6.97(m, 1H), 7.11(d, J=8 Hz,1H), 7.16-7.22(m, 1H), 7.72(s, 1H), 7.92(d, J=3 Hz, 1H), 7.95(d, J=3 Hz,1H)

Example 1033[1-[10-(Methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-4-methylimidazol-5-yl]carboxylicacid

0.4 g of the title compound was obtained as a yellow oily substance bytreating 0.5 g ofethyl[1-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-4-methylimidazol-5-yl]carboxylateby the same method as the one of Example 1032 by conducting the reactionfor 60 hours.

¹H-NMR(DMSO-d₆) δ ppm: 2.34(s, 3H), 3.32(s, 3H), 5.13(s, 2H), 5.47(s,2H), 6.73(dd, J=2, 8 Hz, 1H), 6.88(d, J=2 Hz, 1H), 7.06(d, J=8 Hz, 1H),7.73(s, 1H), 7.93(d, J=3 Hz, 1H), 7.97(d, J=3 Hz, 1H)

Example 1034(E)-3-[1-[10-(Methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-5-methylimidazol-4-yl]-2-methylpropenamide

0.9 g ofethyl(E)-3-[1-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-5-methylimidazol-4-yl]-2-methylpropenoatewas treated by the same method as the one of Example 18 to thereby give0.9 g of(E)-3-[1-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-5-methylimidazol-4-yl]-2-methylpropenoicacid as yellow crystals. To a solution of 0.9 g of these crystals intetrahydrofuran (30 ml) were added at, 0° C. 0.83 ml of triethylamineand 0.57 ml of diethyl chlorophosphate. After stirring for 30 minutes, 5ml of an ammonia-methanol solution was added and the resulting mixturewas reacted at room temperature for 2 hours. Then the reaction mixturewas poured into water, extracted with ethyl acetate, washed with asaturated aqueous solution of sodium chloride and dried over anhydrousmagnesium sulfate. After concentrating under reduced pressure, theresidue was purified by silica gel column chromatography (eluted withmethanol/dichloromethane) to thereby give 0.27 of the title compound asa yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 2.22(s, 3H), 2.51(d, J=1 Hz, 3H), 3.43(s, 3H),5.02(s, 2H), 5.16(s, 2H), 6.62(dd, J=2, 8 Hz, 1H), 6.78(d, J=2 Hz, 1H),6.98(d, J=8 Hz, 1H), 7.40-7.43(m, 1H), 7.57(s, 1H), 7.84(d, J=3 Hz, 1H),7.86(d, J=3 Hz, 1H)

Examples

The following compounds were obtained by treating the compounds obtainedin Examples 1032, 1033 and 1034 by the same method as the one of Example8.

Ex. Structural formula MS M. p. NMR 1035

ESI (+) 339 (MH⁺) >298° C. ¹H-NMR (DMSO-d₆) δ ppm: 2.33(s, 3H), 5.03(s,2H), 6.47(s, 1H), 6.54(d, J=8Hz, 1H), 6.89(d, J=8Hz, 1H), 6.96(br.s,1H), 7.13- 7.25(m, 1H), 7.62(s, 2H), 7.68(br.s, 1H), 9.50(s, 1H) 1036

ESI (+) 340 (MH⁺)   235° C. (decompose) ¹H-NMR (DMSO-d₆) δ ppm: 2.37(s,3H), 5.32(s, 2H), 6.49(s, 1H), 6.47-6.52(m, 1H), 6.86(d, J=8Hz, 1H),7.64(s, 2H), 7.97(s, 1H), 9.51(s, 1H) 1037

ESI (+) 379 (MH⁺)   280° C. (decompose) ¹H-NMR (DMSO-d₆) δ ppm: 2.11(s,3H), 2.28(s, 3H), 5.03(s, 2H), 6.49(s, 1H), 6.53(d, J=8Hz, 1H), 6.75-6.90(m, 1H), 6.88(d, J=8Hz, 1H), 7.06(s, 1H), 7.35-7.40(m, 1H), 7.62(s,2H), 7.74(s, # 1H), 9.51(s, 1H)

Example 1038[1-[10-(Methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-5-methylimidazol-4-yl]carbaldehyde

0.22 g of the title compound was obtained as yellow crystals by treating0.68 g of[1-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-5-methylimidazol-4-yl]methanolwith manganese dioxide by the same method as the one of Example 173.

¹H-NMR(CDCl₃) δ ppm: 2.49(s, 3H), 3.45(s, 3H), 5.04(s, 2H), 5.18(s, 2H),6.63-6.69(m, 1H), 6.80(m, 1H), 7.01(d, J=8 Hz, 1H), 7.53(s, 1H), 7.85(d,J=3 Hz, 1H), 7.87(d, J=3 Hz, 1H), 9.98(s, 1H)

Examples

The following compounds were obtained by the same method as the one ofProduction Example 25 by starting with[1-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-5-methylimidazol-4-yl]carbaldehydeand various Wittig-Horner-Emmons reagents.

Ex. Structural formula NMR 1039

¹H-NMR (CDCl₃) δ ppm: 1.33(t, J=7Hz, 3H), 2, 21(s, 3H), 2.49(d, J=1Hz,3H), 3.43(s, 3H), 4.25(q, J=7Hz, 2H), 5.03(s, 2H), 5.15(s, 2H),6.61-6.50(m, 1H), 6.72-6.76(m, 1H), 6.98(d, J=8Hz, 1H), 7.46- 7.48(m,1H), 7.59(s, 1H), 7.85(d, J=3Hz, 1H), 7.86(d, J=3Hz, 1H) 1040

¹H-NMR (CDCl₃) δ ppm: 0.87(t, J=7Hz, 3H), 1.2- 1.4(m, 15H), 1.45-1.57(m,2H), 2.20(s, 3H), 3.0-3.1(m, 2H), 3.42(s, 3H), 4.24(q, J= 7Hz, 2H),5.01(s, 2H), 5.15 (s, 2H), 6.63(dd, J=1, 8Hz, 1H), 6.74(d, J=1Hz, 1H),6.98 (d, J=8Hz, 1H), 7.42(s, 1H), 7.54(s, 1H), 7.84(d, J=3Hz, # 1H),7.86(d, J=3Hz, 1H)

Examples

1.2 g of[1-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-4-methylimidazol-5-yl]carbaldehydewas obtained from 1.6 g of[1-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-4-methylimidazol-5-yl]methanolby the same method as the one of Example 173. Next, the obtained productwas treated with various Wittig-Horner-Emmons reagents similar toProduction Example 25 to thereby give the following compounds.

Ex. Structural formula NMR 1041

¹H-NMR (DMSO-d₆) δ ppm: 1.17(t, J=7Hz, 3H), 1.74(s, 3H), 1.99(s, 3H),3.29(s, 3H), 4.10(q, J=7Hz, 2H), 5.08(s, 2H), 5.12(s, 2H), 6.69(dd, J=1,8Hz, 1H), 6.78(d, J=1Hz, 1H), 7.08(d, J=8Hz, 1H), 7.21(s, 1H), 7.83(s,1H), 7.92(d, J=3Hz, 1H), 7.95(d, J=3Hz, 1H) 1042

¹H-NMR (DMSO-d₆) δ ppm: 0.73(t, J=7Hz, 3H), 1.18(t, J=8Hz, 3H), 1.99(s,3H), 2.13(q, J=8Hz, 2H), 3.30(s, 3H), 4.12(q, J=8Hz, 2H), 5.07(s, 2H),5.13(s, 2H), 6.68(d, J=8Hz, 1H), 6.80(s, 1H), 7.07(dd, J=1, 8Hz, 1H),7.11(s, 1H), 7.83(s, 1H), 7.90-7.94 (m, 1H), 7.94-7.98(m, 1H)

Example 1043(E)-2-Hydroxy-5-[1-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-5-methylimidazol-4-yl]-2-methyl-4-penten-3-one

0.7 g of the title compound was obtained as a yellow oily substance byreacting 0.5 g of[1-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-5-methylimidazol-4-yl]carbaldehydewith 2.1 ml of 3-hydroxy-3-methyl-2-butanone in the presence of lithiumhydroxide by the same method as the one of Example 1203.

¹H-NMR(CDCl₃) δ ppm: 1.45(s, 6H), 2.25(s, 3H), 3.43(s, 3H), 5.01(s, 2H),5.17(s, 2H), 6.60-6.65(m, 1H), 6.80(s, 1H), 6.98(d, J=8 Hz, 1H), 7.15(d,J=16 Hz, 1H), 7.55(s, 1H), 7.77(d, J=16 Hz, 1H), 7.80-7.88(m, 2H)

Example 10442-Hydroxy-5-[1-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,41-benzothiazin-8-ylmethyl]-5-methylimidazol-4-yl]-2-methyl-4-pentan-3-one

The title compound was obtained by hydrogenating(E)-2-hydroxy-5-[1-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-5-methylimidazol-4-yl]-2-methyl-4-penten-3-oneby the same method as the one of Example 20.

¹H-NMR(CDCl₃) δ ppm: 1.33(s, 6H), 2.04(s, 3H), 2.86(t, J=7 Hz, 2H),2.99(t, J=7 Hz, 2H), 3.45(s, 3H), 3.49(s, 1H), 4.94(s, 2H), 5.17(s, 2H),6.60(dd, J=2, 8 Hz, 1H), 6.78(d, J=2 Hz, 1H), 6.97(d, J=8 Hz, 1H),7.39(s, 1H), 7.84(d, J=3 Hz, 1H), 7.86(d, J=3 Hz, 1H)

Example 1045Ethyl(E)-3-[1-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl-methyl)imidazol-2-yl]propenoate

The title compound was obtained by treating1-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)imidazol-2-carbaldehydesuccessively by the same methods as those described in ProductionExample 25 and Example 9.

¹H-NMR(DMSO-d₆) δ ppm: 1.20(t, J=7 Hz, 3H), 4.11(q, J=7 Hz, 2H), 5.25(s,2H), 6.50(d, J=1 Hz, 1H), 6.52(dd, J=1, 8 Hz, 1H), 6.56(d, J=16 Hz, 1H),6.87(d, J=8 Hz, 1H), 7.12(s, 1H), 7.34(s, 1H), 7.47(d, J=16 Hz, 1H),7.63(s, 2H), 9.55(s, 1H)

MS: ESI(+)402.1(MNa⁺)

m.p.: 213-215° C.

Examples

The following compounds were obtained by the same treatments as those ofExamples 18 and 8.

Ex. Structural formula MS M. p. NMR 1046

ESI (+) 380 (MH⁺) >290° C. ¹H-NMR (DMSO-d₆) δ ppm: 2.12(s, 3H), 2.27(s,3H), 5.04(s, 2H), 6.48(s, 1H), 6.50-6.60(m, 1H), 6.88(d, J=8Hz, 1H),7.32(s, 1H), 7.62(s, 2H), 7.79(s, 1H), 9.49(s, 1H) 1047

ESI (+) 394 (MH⁺) >288° C. (decom- pose) ¹H-NMR (DMSO-d₆) δ ppm: 0.99(t,J=8Hz, 3H), 2.13(s, 3H), 2.90(q, J=8Hz, 2H), 5.04(s, 2H), 6.50(s, 1H),6.57(d, J=8Hz, 1H), 6.89(dd, J=2, 8Hz, 1H), 7.28(d, J=2Hz, 1H),7.60-7.64(m 2H), # 7.79(d, J=2Hz, 1H), 9.50(s, 1H) 1048

ESI (+) 466 (MH⁺) 202- 204° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.11(s, 6H),1.48-1.60(m, 2H), 2.13(s, 3H), 2.8- 2.93(m, 2H), 3.12(s, 3H), 5.03(s,2H), 6.51(d, J=2Hz, 1H), 6.58(dd, J=2, 8Hz, 1H), 6.89(d, J=8Hz, 1H),7.30(s, 1H), 7.62(s, # 2H), 7.77(s, 1H), 9.50(s, 1H) 1049

ESI (+) 492 (MH⁺) 194- 197° C. ¹H-NMR (DMSO-d₆) δ ppm: 0.81(t, J=8Hz,3H), 1.18(br.s, 13H), 1.3- 1.43(m, 2H), 2.13(s, 3H), 2.6-2.78(m, 2H),5.13(s, 2H), 6.53(d, J=1Hz, 1H), 6.61(d, J=8Hz, 1H), 6.89(d, J=8Hz, 1H),7.26(s, 1H), 7.62(s, 2H), # 8.2-8.5(m, 1H), 9.52(s, 1H) 1050

ESI (+) 380 (MH⁺) >298° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.71(d, J=1Hz, 3H),1.99(s, 3H), 4.96(s, 2H), 6.41(s, 1H), 6.38-6.46(m, 1H), 6.84(d, J=8Hz,1H), 7.12(s, 1H), 7.61(s, 2H), 7.75(s, 2H), 9.51(s, 1H) 1051

ESI (+) 394 (MH⁺)   172° C. ¹H-NMR (DMSO-d₆) δ ppm: 0.78(t, J=8Hz, 3H),2.00- 2.20(m, 2H), 2.13(s, 3H), 5.15(s, 2H), 6.40-6.45(m, 1H),6.55-6.63(m, 1H), 6.88(d, J=8Hz, 1H), 7.00(s, 1H), 7.63(s, 2H), 8.90(m,1H), 9.49(s, 1H)

Example 1052(E)-3-[1-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)imidazol-2-yl]propenoicacid

The title compound was obtained by treatingethyl(E)-3-[1-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)imidazol-2-yl]propenoateby the same method as the one of Example 18.

¹H-NMR(DMSO-d₆) δ ppm: 5.26(s, 2H), 6.46(d, J=1 Hz, 1H), 6.50(dd, J=1, 8Hz, 1H), 6.52(d, J=16 Hz, >1H), 6.88(d, J=8 Hz, 1H), 7.12(s, 1H),7.37(d, J=16 Hz, 1H), 7.39(s, 1H), 7.62(s, 2H), 9.52(s, 1H)

MS: ESI(+)352.2(MH⁺)

m.p.: 243-244° C.

Example 10531-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)imidazol-2-carboxylicacid

To a solution of 177 mg of1-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)imidazol-2-carbaldehydein a mixture of tetrahydrofuran (10 ml) with ethanol (10 ml) were added0.5 ml of an aqueous solution of 0.24 g of silver nitrate and 1.5 Nsodium hydroxide (4 ml) and the resulting mixture was stirred at roomtemperature for 15 hours. After filtering off the insoluble matters, thesolution was concentrated under reduced pressure and the crystals of1-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)imidazol-2-carboxylicacid thus precipitated were taken up by filtration. Next, the crystalswere treated by the same method as the one of Example 9 to thereby give55 mg of the title compound as orange crystals.

¹H-NMR(DMSO-d₆) δ ppm: 5.61(s, 2H), 6.56(d, J=8 Hz, 1H), 6.65(s, 1H),6.78(s, 1H), 6.81(d, J=8 Hz, 1H), 7.05(s, 1H), 7.61(s, 2H), 9.55(s, 1H)

MS: ESI(+)281(M⁺−CO₂)

m.p.: 219-220° C.

Example 1054N-[2-[1-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-imidazol-4-yl]ethyl]methanesulfonamide

0.5 g of10-methoxymethyl-8-chloromethyl-10H-pyrazino-[2,3-b][1,4]benzothiazineand 1.0 g of 4-(2-aminoethyl)imidazole dihydorchloride were treated bythe same method as the one of Example 1094 to thereby give 0.7 g ofcrude8-[4-(2-aminoethyl)imidazol-1-yl]-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazineas a brown solid. This crude product was then treated by the same methodas the one of Example 316 to thereby give 0.1 g ofN-[2-[1-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4benzothiazin-8-ylmethyl)imidazol-4-yl]ethyl]methanesulfonamide.Further, it was treated by the same method as the one of Example 8 tothereby give 50 mg of the title compound as yellow crystals.

¹H-NMR(CDCl₃) δ ppm: 2.80(t, J=6 Hz, 2H), 2.94(s, 3H), 3.44(q, J=6 Hz,2H), 4.92(s, 2H), 5.40-5.50(m, 1H), 6.20(d, J=2 Hz, 1H), 6.64(dd, J=2, 8Hz, 1H), 6.73(d, J=1 Hz, 1H), 6.86(d, J=8 Hz, 1H), 6.90-6.98(m, 1H),7.44(d, J-1 Hz, 1H), 7.56(d, J=3 Hz, 1H), 7.68(d, J=3 Hz, 1H)

MS: ESI(+)403(MH⁺)

m.p.: 173-176° C.

Example 1055N-[2-[1-[10-(Methoxymethyl)-10H-pyrazino[2,3-b][1,4]-benzothiazin-8-ylmethyl]imidazol-4-yl]ethyl]sulfamide

0.25 g of the title compound was obtained as yellow crystals by treating1.0 g of8-[4-(2-aminoethyl)imidazol-1-yl]-10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]-benzothiazineand 0.23 g of sulfamide by the same method as the one of Example 326.

¹H-NMR(DMSO-d6) δ ppm: 2.62(t, J=BHz, 2H), 3.02-3.10(m, 2H), 3.33(s,3H), 5.06(s, 2H), 5.19(s, 2H), 6.50(s, 3H), 6.85(dd, J=1, 8 Hz, 1H),6.92(s, 1H), 6.95(m, 1H), 7.10(d, J=8 Hz, 1H), 7.63(s, 1H), 7.92(d, J=3Hz, 1H), 7.95(d, J=3 Hz, 1H)

Example 1056N-[2-[1-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-imidazol-4-yl]ethyl]sulfamide

The title compound was obtained as yellow crystals by treatingN-[2-[1-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]-benzothiazin-8-ylmethyl]imidazol-4-yl]ethyl]sulfamideby the same method as the one of Example 8.

¹H-NMR(DMSO-d₆) δ ppm: 2.58-2.65(m, 3H), 3.02-3.10(m, 2H), 4.95(s, 2H),6.50(br.s, 3H), 6.58(d, J=2 Hz, 1H), 6.60-6.65(m, 1H), 6.85(s, 1H),6.88(d, J=8 Hz, 1H), 7.59(s, 1H), 7.63(s, 2H)

MS: ESI(+)404(MH⁺)

m.p.: 187-189° C.

Example 10578-[4-(4-Nitrophenyl)imidazol-1-ylmethyl]-10-methoxymethyl-10H-pyrazino[]2,3-b][1,4]benzothiazine

The title compound was synthesized by treating8-chloromethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazineand 4-(4-nitrophenyl)imidazole by the same method as the one of Example1094.

¹H-NMR(CDCl₃) δ ppm: 3.43(s, 3H), 5.09(s, 2H), 5.22(s, 2H), 6.81(dd,J=2, 8 Hz, 1H), 6.96(d, J=2 Hz, 1H), 7.03(d, J=8 Hz, 1H), 7.34(d, J=1Hz, 1H), 7.65(d, J=1 Hz, 1H), 7.84(d, J=3 Hz, 1H), 7.87(d, J=3 Hz, 1H),7.89(m, 2H), 8.22(m, 2H)

Example 10588-[4-(4-Aminophenyl)imidazol-1-ylmethyl]-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine

The title compound was obtained by hydrogenating8-[4-(4-nitrophenyl)imidazol-1-ylmethyl]-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazineby the same method as the one of Example 20.

¹H-NMR(CDCl₃) δ ppm: 3.42(s, 3H), 3.67(br.s, 2H), 5.05(s, 2H), 5.18(s,2H), 6.69(m, 2H), 6.78(dd, J=2, 8 Hz, 1H), 6.89(d, J=2 Hz, 1H), 6.99(d,J=8 Hz, 1H), 7.04(d, J=2 Hz, 1H), 7.54(d, J=2 Hz, 1H), 7.55(m, 2H),7.83(d, J=3 Hz, 1H), 7.85(d, J=3 Hz, 1H)

Examples

The following compounds were obtained by treating8-[4-(4-aminophenyl)imidazol-1-ylmethyl]-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazineby the same method as the one of Example 316.

Ex. Structural formula NMR 1059

¹H-NMR (CDCl₃) δ ppm: 2.99(s, 3H), 3.43(s, 3H), 5.08(s, 2H), 5.20(s,2H), 6.51(br.s, 1H), 6.79(dd, J=2, 8Hz, 1H), 6.93(d, J=2Hz, 1H), 7.01(d,J=8Hz, 1H), 7.16(d, J=1Hz, 1H), 7.21(d, J=8Hz, 2H), 7.61(d, J=1Hz, 1H),7.73(d, J=8Hz, 2H), 7.84(d, J=3Hz, 1H), # 7.86(d, J=3Hz, 1H) 1060

¹H-NMR (CDCl₃) δ ppm: 2.18(s, 3H), 3.42 (s, 3H), 5.07(s, 2H), 5.19(s,2H), 6.80(dd, J=2, 8Hz, 1H), 6.92(d, J=2Hz, 1H), 7.02(d, J=8Hz, 1H),7.04(m, 2H), 7.19(d, J=1Hz, 1H), 7.62(d, J=1Hz, 1H), 7.76(m, 2H), 7.83-7.85(m, 2H)

Example 1061¹N-[4-[1-(10-Methoxymethyl-10H-pyrazino[2,3-b][1,41-benzothiazin-8-ylmethyl)imidazol-4-yl]phenyl]-N²-methanesulfonyl-formamidine

The title compound was obtained by treating8-[4-(4-aminophenyl)imidazol-1-ylmethyl]-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazineby the same method as the one of Example 328.

¹H-NMR(CDCl₃) δ ppm: 3.03 and 3.05(s, total 3H), 3.43(s, 3H), 5.07(s,2H), 5.20(s, 2H), 6.80(dd, J=2, 8 Hz, 1H), 6.84(d, J=2 Hz, 1H), 7.01(d,J=8 Hz, 1H), 7.11 and 7.65(d, J=8 Hz, total 2H), 7.18(d, J=1 Hz, 1H),7.61(d, J=1 Hz, 1H), 7.75 and 7.77(d, J=8 Hz, total 2H), 7.84(d, J=3 Hz,1H), 7.86(d, J=3 Hz, 1H), 7.98 and 8.01(s, total 1H), 8.67 and 8.71(s,total 1H)

Examples

The following compounds were obtained by treating the compounds obtainedin Examples 1059, 1060 and 1061 by the same method as the one of Example9.

Ex. Structural formula MS M. p. NMR 1062

ESI (+) 451.1 (MH⁺) 253-255° C. ¹H-NMR (DMSO-d₆) δ ppm: 2.97(s, 3H),5.05(s, 2H), 6.62(d, J=1Hz, 1H), 6.67(dd, J=1, 7Hz, 1H), 6.90(d, J=7Hz,1H), 7.16(d, J=8Hz, 2H), 7.53(d, J=1Hz, 1H), 7.63(s, 2H), 7.68(d, J=8Hz,2H), 7.74(d, J=1Hz, 1H), 9.53(s, 1H), 9.65(s, 1H) 1063

FAB (+) 415 (M⁺) 261-263° C. ¹H-NMR (DMSO-d₆) δ ppm: 2.02(s, 3H),5.04(s, 2H), 6.62(d, J=1Hz, 1H), 6.68(dd, J=1, 7Hz, 1H), 6.90(d, J=7Hz,1H), 7.49(s, 1H), 7.53(d, J=8Hz, 2H), 7.63(s, 2H), 7.64(d, J=8Hz, 2H),7.74(s, 1H), 9.53(s, 1H), 9.79(s, 1H) 1064

FAB (+) 478 (M⁺) 159-162° C. ¹H-NMR (DMSO-d₆) δ ppm: 3.30(s, 3H),5.06(s, 2H), 6.61(d, J=1Hz, 1H), 6.69(dd, J=1, 7Hz, 1H), 6.91(d, J=7Hz,1H), 7.24(d, J=8Hz, 1H), 7.57(s, 1H), 7.62(s, 2H), 7.65(d, J=8Hz, 2H),7.74(d, J=8Hz, 2H), 7.75(d, J=8Hz, 1H), 8.08(s, # 1H), 9.52(s, 1H)

Example 1065N-[⁴-[1-(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)imidazol-4-yl]phenyl]hexahydro-2-oxo-1H-thieno[3,4-d]imidazole-4-pentanamide

104 mg of8-[4-(4-aminophenyl)imidazol-1-ylmethyl3-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazineand 91 mg of hexahydro-2-oxo-1H-thieno(3,4-dlimidazole-4-pentanoic acidwere treated by the same method as the one of Example 1294.Then theobtained product was purified by using a preparative silica gel plate tothereby give 72 mg of the title compound as yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 1.4-1.6(m, 6H), 2.28(t, J=6 Hz, 2H), 2.56(d, J=7Hz, 1H), 2.80(dd, J=3, 7 Hz, 1H), 3.10(m, 1H), 3.30(s, 3H), 4.12(m, 1H),4.28(m, 1H), 5.15(s, 2H), 5.20(s, 2H), 6.35(s, 1H), 6.43(s, 1H),6.91(dd, J=2, 8 Hz, 1H), 7.00(d, J=2 Hz, 1H), 7.12(d, J=8 Hz, 1H),7.54(d, J=8 Hz, 2H), 7.55(d, J=1 Hz, 1H), 7.63(d, J=8 Hz, 2H), 7.77(d,J=1 Hz, 1H), 7.92(d, J=3 Hz, 1H), 7.98(d, J=3 Hz, 1H), 9.84(s, 1H)

Example 1066N-[4-[1-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)imidazol-4-yl]phenyl]-hexahydro-2-oxo-1H-thieno[3,4-d]-imidazole-4-pentanamide

The title compound was obtained by treatingN-[4-[1-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)imidazol-4-yl]phenyl]-hexahydro-2-oxo-1H-thieno[3,4-d]imidazole-4-pentanamideby the same method as the one of Example 9.

¹H-NMR(DMSO-d,) δ ppm: 1.4-1.6(m, 6H), 2.28(t, J=6 Hz, 2H), 2.46(d, J=7Hz, 1H), 2.80(dd, J=3, 7 Hz, 1H), 3.10(m, 1H), 4.09(m, 1H), 4.28(m, 1H),5.15(s, 2H), 6.35(s, 1H), 6.43(s, 1H), 6.91(dd, J=1, 6 Hz, 1H), 7.00(d,J=1 Hz, 1H), 7.12(d, J=6 Hz, 1H), 7.54(d, J=5 Hz, 2H), 7.54(s, 1H),7.63(d, J=5 Hz, 2H), 7.77(d, J=1 Hz, 1H), 7.92(d, J=2 Hz, 1H), 7.95(d,J=2 Hz, 1H), 9.53(s, 1H), 9.85(s, 1H)

MS: FAB(+)599(M⁺)

Example 1067N-[2-[1-[10-(Methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)imidazol-4-yl]ethyl]-5-methyl-1,2oxazole-4-carboxamide

0.5 g of the title compound was obtained as a yellow oily substance bydehydrating/condensing 1.5 g of8-[4-(4-aminoethyl)imidazol-1-ylmethyl]-10H-pyrazino[2,3-b][1,4]benzothiazinewith 1.5 g of 5-methyl-1,2-oxazole-4-carboxylic acid by the same methodas the one of Example 1294.

¹H-NMR(DMSO-d₆) δ ppm: 2.58(s, 3H), 2.64(t, J=6 Hz, 2H), 3.32(s, 3H),3.34-3.42(m, 2H), 5.07(s, 2H), 5.19(s, 2H), 6.80-6.86(m, 1H),6.90-6.96(m, 2H), 7.07(d, J=8 Hz, 1H), 7.62-7.66(m, 1H), 7.92(d, J=3 Hz,1H), 7.95(d, J=3 Hz, 1H), 8.33(t, J=6 Hz, 1H), 8.80(s, 1H)

Example 1068N-[2-[1-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)imidazol-4-yl]ethyl]-5-methyl-1,2-oxazole-4-carboxamide

The title compound was obtained by treatingN-[2-[1-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)imidazol-4-yl]ethyl]-5-methyl-1,2-oxazole-4-carboxamideby the same method as the one of Example 8.

¹H-NMR(DMSO-d₆) δ ppm: 2.59(s, 3H), 2.64(t, J=8 Hz, 2H), 3.3-3.45(m,2H), 4.95(s, 2H), 6.56(m, 1H), 6.6-6.65(m, 1H), 6.85(d, J=8 Hz, 1H),6.88(br.s, 1H), 7.63(s, 3H), 8.33(t, J=6 Hz, 1H), 8.90(s, 1H), 9.51(s,1H)

MS: ESI(+)434(MH⁺)

m.p.: 165-167° C.

Example 1069N-[2-[1-[10-(Methoxymethyl)-10H-pyrazino[2,3-b][1,4]-benzothiazin-8-ylmethyl]imidazol-4-yl]phenyl]-5-methyl-1,2-oxazole-4-carboxamide

The title compound was obtained as a yellow oily substance bydehydrating/condensing 1.5 g of8-[4-(4-aminophenyl)imidazol-1-ylmethyl]-10H-pyrazino[2,3-b][1,4]benzothiazinewith 5-methyl-1,2-oxazole-4-carboxylic acid by the same method as theone of Example 1294.

¹H-NMR(CDCl₃) δ ppm: 2.77(s, 3H), 3.43(s, 3H), 5.07(s, 2H), 5.19(s, 2H),6.80(dd, J=2, 8 Hz, 1H), 6.93(d, J=2 Hz, 1H), 7.01(d, J=8 Hz, 1H),7.17(d, J=1 Hz, 1H), 7.49(br.s, 1H), 7.56(br.d, J=8 Hz, 2H), 7.59(d, J=1Hz, 1H), 7.75(d, J=8 Hz, 2H), 7.84(d, J=3 Hz, 1H), 7.86(d, J=3 Hz, 1H),8.46(br.s, 1H)

Example 1070N-[2-[1-(10H-Pyrazino[2,3-b][1,4]benzothiazin-⁸-ylmethyl)-imidazol-4-yl]phenyl]-2-cyano-3-oxobutanamide

The title compound was obtained by treatingN-[2-[1-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]-benzothiazin-8-ylmethyl]imidazol-4-yl]phenyl]-5-methyl-1,2-oxazole-4-carboxamidesuccessively by the same methods as those of Examples 9 and 505.

¹H-NMR(DMSO-d₆) δ ppm: 2.66(s, 3H), 5.05(s, 2H), 6.62(d, J=1 Hz, 1H),6.70(d, J=1, 7 Hz, 1H), 6.91(d, J=7 Hz, 1H), 7.54(d, J=1 Hz, 1H),7.62(s, 2H), 7.64(d, J=8 Hz, 2H), 7.72(d, J=8 Hz, 2H), 7.75(d, J=1 Hz,1H), 9.05(s, 1H), 9.52(s, 1H), 10.00(s, 1H)

MS: FAB(+)482(M⁺)

m.p.: 259-261° C.

Example 1071[1-(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)imidazol-2-yl]-(2-pyridyl)methanol

The title compound was obtained by treating[1-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)imidazol-2-yl](2-pyridyl)ketoneby the same method as the one of Example 628.

¹H-NMR(CDCl₃) δ ppm: 3.43(s, 3H), 5.12(s, 4H), 5.40(br.s, 1H), 6.00(s,1H), 6.64(dd, J=2, 8 Hz, 1H), 6.67(d, J=2 Hz, 1H), 6.85(d, J=8 Hz, 1H),6.85(d, J=1 Hz, 1H), 7.04(d, J=1 Hz, 1H), 7.13(ddd, J=2, 5, 8 Hz, 1H),7.23-7.25(m, 1H), 7.59(dt, J=2, 8 Hz, 1H), 7.84(d, J=3 Hz, 1H), 7.85(d,J=3 Hz, 1H), 8.45(ddd, J=1, 2, 5 Hz, 1H)

Example 1072[1-(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)imidazol-2-yl]methanol

The title compound was obtained by treating1-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)imidazole-2-carbaldehydeby the same method as the one of Example 628.

¹H-NMR(CDCl₃) δ ppm: 1.80(br.s, 1H), 3.48(s, 3H), 4.66(s, 2H), 5.14(s,2H), 5.19(s, 2H), 6.73(dd, J=2, 8 Hz, 1H)., 6.88(d, J=2 Hz, 1H), 6.89(s,1H), 6.98(d, J=8 Hz, 1H), 6.99(s, 1H), 7.83(d, J=3 Hz, 1H), 7.85(d, J=3Hz, 1H)

Example 1073 Methyl4-[[1-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)imidazol-2-yl]hydroxymethyl]benzoate

The title compound was obtained by treating methyl4-[1-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)imidazol-2-ylcarbonyl]benzoateby the same method as the one of Example 628.

¹H-NMR(CDCl) δ ppm: 3.43(s, 3H), 3.87(s, 3H), 4.80(d, J=16 Hz, 1H),4.91(d, J=16 Hz, 1H), 5.09(d, J=10Hz, 1H), 5.13(d, J=10Hz, 1H), 5.90(s,1H), 6.48(dd, J=2, 8 Hz, 1H), 6.61(d, J=2 Hz, 1H), 6.86(d, J=8 Hz, 1H),6.87(d, J=1 Hz, 1H), 7.06(d, J=1 Hz, 1H), 7.36(d, J=8 Hz, 2H), 7.83(d,J=3 Hz, 1H), 7.85(d, J=3 Hz, 1H), 7.94(d, J=8 Hz, 2H)

Example 10744-[[1-(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)imidazol-2-yl]hydroxymethyl]benzoicacid

The title compound was obtained by treating methyl4-[[1-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)imidazol-2-yl]hydroxymethyl]benzoateby the same method as the one of Example 18.

¹H-NMR(CDCl₃) δ ppm: 3.48(s, 3H), 4.95(d, J=16 Hz, 1H), 5.04(d, J=16 Hz,1H), 5.13(d, J=10Hz, 1H), 5.17(d, J=10Hz, 1H), 5.98(s, 1H), 6.58(dd,J=2, 8 Hz, 1H), 6.72(s, 1H), 6.89-6.91(m, 2H), 7.13(s, 1H), 7.36(d, J=8Hz, 2H), 7.83(s, 2H), 7.89(d, J=8 Hz, 2H)

Examples

The following compounds were obtained by treating the compounds obtainedin Examples 1071, 1072 and 1074 by the same method as the one of Example9.

Ex. Structural formula MS M. p. NMR 1075

FAB (+) 389 (MH⁺) 95-98° C. ¹H-NMR (DMSO-d₆) δ ppm: 5.09(s, 2H), 5.78(d,J=6Hz, 1H), 6.26(d, J=6Hz, 1H), 6.46(dd, J=1, 8Hz, 1H), 6.54(d, J=1Hz,1H), 6.78(s, 1H), 6.82(d, J=8Hz, 1H), 7.04(s, 1H), 7.22(dd, J=6, 9Hz,1H), 7.57(d, J=9Hz, 1H), 7.63(s, 2H), 7.75(dt, # J=2, 9Hz, 1H), 8.48(dd,J=2, 6Hz, 1H), 9.51(s, 1H) 1076

ESI (+) 312.2 (MH⁺) 247-250° C. ¹H-NMR (DMSO-d₆) δ ppm: 4.41(d, J=6Hz,2H), 5.06(s, 2H), 5.31(t, J=6Hz, 1H), 6.57(d, J=9Hz, 1H), 6.58(s, 1H),6.80(s, 1H), 6.87(d, J=9Hz, 1H), 7.07(s, 1H), 7.63(s, 2H), 9.51(s, 1H)1077

FAB (+) 432 (MH⁺) 240-241° C. ¹H-NMR (DMSO-d₆) δ ppm: 4.98(d, J=15Hz,1H), 5.05(d, J=15Hz, 1H), 5.88(d, J=6Hz, 1H), 6.36(d, J=6Hz, 1H),6.44(d, J=8Hz, 1H), 6.45(s, 1H), 6.78(d, J=8Hz, 1H), 6.84(s, 1H),7.05(s, 1H), 7.35(d, J=9Hz, 2H), 7.63(s, 2H), 7.81(d, # 2H), J=9Hz, 2H),9.45(s, 1H)

Example 1078[1-[10-(Methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-5-methylimidazol-4-yl]methanol

The title compound was obtained by treatingethyl[1-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-5-methylimidazol-4-yl]carboxylateby the same method as the one of Example 3.

¹H-NMR(CDCl₃) δ ppm: 2.13(s, 3H), 3.46(s, 3H), 4.58(s, 2H), 4.98(s, 2H),5.18(s, 2H), 6.64(dd, J=2, 8 Hz, 1H), 6.77(d, J=2 Hz, 1H), 6.98(d, J=8Hz, 1H), 7.45-7.51(m, 1H), 7.84(d, J=3 Hz, 1H), 7.86(d, J=3 Hz, 1H)

Example 1079[1-[10-(Methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-4-methylimidazol-5-yl]methanol

The title compound was obtained by treatingethyl[1-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-4-methylimidazol-5-yl]carboxylateby the same method as the one of Example 3.

¹H-NMR(CDCl₃) δ ppm: 2.25(s, 3H), 3.46(s, 3H), 4.51(s, 2H), 5.14(s, 2H),5.19(s, 2H), 6.70-6.76(m, 1H), 6.84-6.87(m, 1H), 6.98-7.00(m, 2H),7.84(d, J=3 Hz, 1H), 7.86(d, J=3 Hz, 1H)

Examples

The following compounds were obtained by treating the compounds obtainedin Examples 1078 and 1079 by the same method as the one of Example 434.

Ex. Structural formula MS M. p. NMR 1080

ESI (+) 326 (MH⁺) >270° C. (decompose) ¹H-NMR (DMSO-d₆) δ ppm: 2.04(s,3H), 4.28(s, 2H), 4.60(s, 1H), 4.96(s, 2H), 6.54(d, J=8Hz, 1H), 6.55(s,1H), 6.89(d, J=8Hz, 1H), 7.55(s, 1H), 7.64(s, 2H), 9.54(s, 1H) 1081

ESI (+) 326 (MH⁺) 188-192° C. ¹H-NMR (DMSO-d₆) δ ppm: 2.08(s, 3H),4.25(d, J=5Hz, 2H), 4.91(t, J=5Hz, 1H), 5.02(s, 2H), 6.50-6.60(m, 2H),6.88(d, J=8Hz, 1H), 7.53(s, 1H), 7.64(s, 2H), 9.57(s, 1H)

Example 10822-[1-[10-(Methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-5-methylimidazol-4-yl]-2-propanol

0.49 g of the title compound was obtained as a yellow oily substance bytreating 0.7 g of ethyl[1-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-5-methylimidazol-4-yl]carboxylatewith methylmagnesium bromide by the same method as the one of ProductionExample 86.

¹H-NMR(CDCl₃) ppm: 1.58(s, 6H), 2.21(s, 3H), 3.46(s, 3H), 4.97(s, 2H),5.17(s, 2H), 6.64(d, J=8 Hz, 1H), 6.75(d, J=1 Hz, 1H), 6.98(dd, J=1, 8Hz, 1H), 7.40(s, 1H), 7.84(dd, J=1, 3 Hz, 1H), 7.85(dd, J=1, 3 Hz, 1H)

Example 10832-[1-[10-(Methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-4-methylimidazol-5-yl]-2-propanoland[1-[10-(methoxymethyl)-10H-pyrazino(2,3-b][1,4]benzothiazin-8-ylmethyl]-4-methylimidazol-5-yl]methylketone

0.7 g ofethyl[1-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-4-methylimidazol-5-yl]-carboxylatewas treated with methylmagnesium bromide by the same method as the oneof Production Example 86. Thus, 0.4 g of2-[1-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-4-methylimidazol-5-yl]-2-propanoland 80 mg of[1-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-4-methylimidazol-5-yl]methylketone were obtained each as yellow crystals.

2-[1-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-4-methylimidazol-5-yl]-2-propanol

¹H-NMR(CDCl₃) δ ppm: 1.59(s, 6H), 2.34(s, 3H), 3.48(s, 3H), 5.15(s, 2H),5.39(s, 2H), 6.64(dd, J=2, 8 Hz, 1H), 6.69(d, J=2 Hz, 1H), 6.95(d, J=8Hz, 1H), 7.30(s, 1H), 7.83(d, J=3 Hz, 1H), 7.84(d, J=3 Hz, 1H)

[1-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-4-methylimidazol-5-yl]methylketone

¹H-NMR(DMSO-d₆) δ ppm: 2.40(s, 3H), 2.48(s, 3H), 3.33(s, 3H), 5.13(s,2H), 5.42(s, 2H), 6.73(dd, J=2, 8 Hz, 1H), 6.82(d, J=2 Hz, 1H), 7.06(d,J=8 Hz, 1H), 7.93(d, J=3 Hz, 1H), 7.97(d, J=3 Hz, 1H), 7.98(s, 1H)

Example 10841-[1-[10-(Methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-4-methylimidazol-5-yl]ethanol

The title compound was obtained by treating[1-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-4-methylimidazol-5-yl]methylketone by the same method as the one of Example 628.

¹H-NMR(CDCl1) δ ppm: 1.46(d, J=7 Hz, 3H), 2.30(s, 3H), 3.44(s, 3H),4.94(q, J=7 Hz, 1H), 5.1-5.25(m, 4H), 6.68-6.74(m, 1H), 6.72(s, 1H),6.98(d, J=8 Hz, 1H), 7.40(s, 1H), 7.82(d, J=3 Hz, 1H), 7.85(d, J=3 Hz,1H)

Examples

The following compounds were obtained by treating the compounds obtainedin Examples 1082, 1083 and 1084 by the same method as the one of Example8.

Ex. Structural formula MS M.p. NMR 1085

ESI (+) 354 (MH⁺) 264-266° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.34(s, 6H),2.18(s, 3H), 4.60(s, 1H), 4.93(s, 2H), 6.54(d, J=7Hz, 1H), 6.57(s, 1H),6.89(d, J=8Hz, 1H), 7.49(s, 1H), 7.65(s, 2H), 9.55(s, 1H) 1086

ESI (+) 354 (MH⁺) 199-202° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.41(s, 6H),2.20(s, 3H), 5.12(s, 1H), 5.30(s, 2H), 6.46(dd, J=2, 8Hz, 1H), 6.53(d,J=2Hz, 1H), 6.87(d, J=8Hz, 1H), 7.38(s, 1H), 7.64(s, 2H), 9.52(s, 1H)1087

ESI (+) 340 (MH⁺) 178-182° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.23(d, J=7Hz, 3H),2.15(s, 3H), 4.75(br.s, 1H), 5.00- 5.20(m, 2H), 6.48-6.56(m, 2H),6.84-6.92(m, 1H), 7.50(m, 1H), 7.64(s, 2H), 9.52(s, 1H)

Example 1088(E)-8-(3-Chloro-1-propen-1-yl)-10-methoxymethyl-10H-pyrazino-[2,3-b][1,4]benzothiazine

2.9 g ofethyl(E)-3-[10-(methoxymethyl)-10H-pyrazino-[2,3-b][1,4]benzothiazin-8-ylmethyl]propenoatewas dissolved in 20 ml of dry dichloromethane in a nitrogen atmosphereand ice-cooled. The reaction mixture was stirred and 5.8 ml of a 1.5 Msolution of isobutylalminum hydride in toluene was dropped thereinto.After stirring for 2 hours, the reaction mixture was poured intoice-ethyl acetate and stirred for 30 minutes. The insoluble matters wereremoved by filtering the reaction mixture thorough celite. Then theorganic layer was extracted, washed with water and dried over anhydroussodium sulfate. After distilling off the solvent under reduced pressure,the residue was purified by silica gel column chromatography (elutedwith ethyl acetate/n-hexane) to thereby give 1.4 g of3-[10-(methoxymethyl)-10H-pyrazino-[2,3-b][1,4]benzothiazin-8-ylmethyl]-2-propen-1-olas a pale yellow oily substance. The obtained compound was dissolved in10 ml of hexachloroacetone and 1.34 g of triphenylphosphine was added inseveral portions thereto under ice-cooling. After stirring at roomtemperature for 30 minutes, the reaction mixture was distributed into anaqueous solution of sodium bicarbonate and diethyl ether and extractedwith ether. After drying over anhydrous sodium sulfate and distillingoff the solvent under reduced pressure, the residue was purified bysilica gel column chromatography (eluted with ethyl acetate/n-hexane) tothereby give 230 mg of the title compound as yellow crystals.

¹H-NMR(CDCl₃) δ ppm: 3.53(s, 3H), 4.23(d, J=7.1 Hz, 2H), 5.27(s, 2H),6.28(dt, J=7.1, 15.6 Hz, 1H), 6.57(d, J=15.6 Hz, 1H), 6.95(d, J=8.1 Hz,1H), 7.00(dd, J=1.7, 8.1 Hz, 1H), 7.15(d, J=1.7 Hz, 1H), 7.83(d, J=3.0Hz, 1H), 7.84(d, J=3.0 Hz, 1H)

Example 1089(E)-8-[3-(1-Imidazolyl)-1-propen-1-yl]-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine

150 mg of the title compound was obtained as yellow crystals by treating200 mg of(E)-8-(3-chloro-1-propen-1-yl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazinewith imidazole by the same method as the one of Example 1094.

¹H-NMR(CDCl₃) δ ppm: 3.54(s, 3H), 4.72(d, J=6.1 Hz, 2H), 5.28(s, 2H),6.25(dt, J=6.1, 15.9 Hz, 1H), 6.43(d, J=15.9 Hz, 1H), 6.95(d, J=8.0 Hz,1H), 6.97(s, 1H), 6.98(dd, J=1.6, 8.0 Hz, 1H), 7.11(s, 1H), 7.13(d,J=1.6 Hz, 1H), 7.56(s, 1H), 7.83(d, J=2.6 Hz, 1H), 7.84(d, J=2.6 Hz, 1H)

Example 1090(E)-8-[3-(1-Imidazolyl)-1-propen-1-yl]-10H-pyrazino[2,3-b][1,4]benzothiazine

The following compound was obtained by treating(E)-8-[3-imidazolyl)-1-propen-1-yl]-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazineby the same method as the one of Example 434.

¹H-NMR(DMSO-d₆) δ ppm: 4.73(d, J=5.3 Hz, 2H), 6.26(td, J=5.3, 15.8 Hz,1H), 6.30(d, J=15.8 Hz, 1H), 6.75(s, 1H), 6.85(d, J=7.8 Hz, 1H), 6.87(d,J=7.8 Hz, 1H), 6.91(s, 1H), 7.16(s, 1H), 7.61-7.63(m, 2H), 7.65(s, 1H),9.45(s, 1H)

Example 10918-[3-(1-Imidazolyl)-1-propyl]-10H-pyrazino[2,3-b][1,4]benzothiazine

Similar to Example 1094,3-[10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl]propylmethanesulfonate was reacted with imidazole and then treated by the samemethod as the one of Example 434 to thereby give the following compound.

¹H-NMR(CDCl₃) δ ppm: 2.06(quintet, J=7.0 Hz, 2H), 2.44(t, J=7.0 Hz, 2H),3.93(t, J=7.0 Hz, 2H), 6.30(d, J=1.8 Hz, 1H), 6.63(dd, J=1.8, 8.0 Hz,1H), 6.82(d, J=8.0 Hz, 1H), 6.86-6.93(br.s, 1H), 6.91(s, 1H), 7.09(s,1H), 7.50(s, 1H), 7.55(d, J=2.9 Hz, 1H), 7.69(d, J=2.9 Hz, 1H)

MS: ESI(+)310.2(MH⁺)

m.p.: 139-141° C.

Example 1092 8-(Imidazol-1-yl)-10H-pyrazino[2,3-b][1,4]benzoxazine

The following compound was obtained by reacting8-chloromethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]-benzoxazinewith imidazole and then treating by the same method as the one ofExample 8.

¹H-NMR(DMSO-d₆) δ ppm: 5.04(s, 2H), 6.46(d, J=2 Hz, 1H), 6.59(dd, J=2, 8Hz, 1H), 6.75(d, J=8 Hz, 1H), 6.87-6.98(m, 1H), 7.10-7.20(m, 1H),7.27(d, J=3 Hz, 1H), 7.47(d, J=3 Hz, 1H), 7.65-7.78(m, 1H), 9.66(s, 1H)

MS: ESI(+)266(MH⁺)

m.p.: 252-255° C.

Example 10934-[1-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)imidazol-4-yl]benzamidine

0.092 g of the title compound was obtained by treating 0.44 g of4-[1-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)imidazol-4-yl]benzonitrileby the same method as the one of Example 1479.

¹H-NMR(DMSO-d,) δ ppm: 5.10(s, 2H), 6.64(d, J=1 Hz, 1H), 6.72(dd, J=1, 7Hz, 1H), 6.93(d, J=7 Hz, 1H), 7.60(d, J=8 Hz, 2H), 7.64(s, 2H), 7.87(s,2H), 7.96(d, J=8 Hz, 2H), 9.51(s, 1H)

MS: FAB(+)399(M⁺)

Example 109410-Methoxymethyl-8-(pyrazol-1-ylmethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine

To a solution of 100 mg of pyrazole in N,N-dimethylformamide was addedin a nitrogen atmosphere 60 mg of sodium hydride (oily 60%) under icecooling and the resulting mixture was stirred for 10 minutes.Subsequently, 240 mg of10-methoxymethyl-8-chloromethyl-10H-pyrazino[2,3-b][1,4]benzothiazinewas added to the reaction mixture, which was then heated to 80° C. for10 minutes. Then the reaction mixture was brought back to roomtemperature and distributed into water and ethyl acetate. The organiclayer was extracted, washed with water and dried over anhydrous sodiumsulfate. After distilling off the solvent under reduced pressure, theresidue thus obtained was purified by silica gel column chromatography(eluted with ethyl acetate/n-hexane) to thereby give 150 mg of the titlecompound as a yellow powder.

¹H-NMR(CDCl₃) δ ppm: 3.47(s, 3H), 5.20(s, 2H), 5.27(s, 2H), 6.30(t,J=2.1 Hz, 1H), 6.79(dd, J=1.6, 7.8 Hz, 1H), 6.82(d, J=1.6 Hz, 1H),6.97(d, J=7.8 Hz, 1H), 7.42(d, J=2.1 Hz, 1H), 7.56(d, J=2.1 Hz, 1H),7.83(d, J=2.9 Hz, 1H), 7.84(d, J=2.9 Hz, 1H)

Example 109510-Methoxymethyl-8-(1H-tetrazol-1-ylmethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine.and10-methoxymethyl-8-(2H-tetrazol-2-ylmethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine

The title compounds were obtained by treating 1H-tetrazole and10-methoxymethyl-8-chloromethyl-10H-pyrazino[2,3-b][1,4]benzothiazine bythe same method as the one of Example 1094.

10-methoxymethyl-8-(1H-tetrazol-1-ylmethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine

¹H-NMR(CDCl₃) δ ppm: 3.51(s, 3H), 5.33(s, 2H), 5.53(s, 2H), 6.88(dd,J=1.5, 8.1 Hz, 1H), 7.04(d, J=8.1 Hz, 1H), 7.07(d, J=1.5 Hz, 1H),7.85(d, J=2.7 Hz, 1H), 7.88(d, J=2.7 Hz, 1H), 8.56(s, 1H)

10-methoxymethyl-8-(2H-tetrazol-2-ylmethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine

¹H-NMR(CDCl₃) δ ppm: 3.52(s, 3H), 5.23(s, 2H), 5.73(s, 2H), 6.97(dd,J=1.6, 7.8 Hz, 1H), 7.01(d, J=7.8 Hz, 1H), 7.15(d, J=1.6 Hz, 1H),7.84(d, J=3.0 Hz, 1H), 7.86(d, J=3.0 Hz, 1H), 8.53(s, 1H)

Example 109610-Methoxymethyl-8-[1H-pyrrolo[2,3-b]pyridin-1-ylmethyl)-10H-pyrazino[2,3-b][1,4]benzothiazineand10-methoxymethyl-8-[1H-pyrrolo[2,3-b]pyridin-³-ylmethyl]-10H-pyrazino[2,3-b][1,4]benzothiazine

The title compounds were obtained by reacting 1H-pyrrolo[2,3-b]pyridinewith10-methoxymethyl-8-chloromethyl-10H-pyrazino[2,3-b][1,4]benzothiazine bythe same method as the one of Example 1094.

10-methoxymethyl-8-[1H-pyrrolo[2,3-b]pyridin-1-ylmethyl]-10H-pyrazino[2,3-b][1,4]benzothiazine

¹H-NMR(CDCl₃) δ ppm: 3.31(s, 3H), 5.09(s, 2H), 5.44(s, 2H), 6.50(d, J=4Hz, 1H), 6.78(dd, J=2, 8 Hz, 1H), 6.91(d, J=2 Hz, 1H), 6.93(d, J=8 Hz,1H), 7.09(dd, J=5, 8 Hz, 1H), 7.20(d, J=4 Hz, 1H), 7.81(d, J=3 Hz, 1H),7.82(d, J=3 Hz, 1H), 7.93(dd, J=1, 8 Hz, 1H), 8.34(dd, J=1, 5 Hz, 1H)

10-methoxymethyl-8-[1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-10H-pyrazino[2,3-b][1,4]benzothiazine

¹H-NMR(CDCl₃) δ ppm: 3.37(s, 3H), 5.13(s, 2H), 5, 84(s, 2H), 6.72(d, J=3Hz, 1H), 6.91(dd, J=6, 8 Hz, 1H), 6.94(dd, J=2, 8 Hz, 1H), 6.98(d, J=8Hz, 1H), 7.15(d, J=2 Hz, 1H), 7.60(d, J=6 Hz, 1H), 7.83(d, J=3 Hz, 1H),7.84(d, J=3 Hz, 1H), 7.92(d, J=3 Hz, 1H), 8.13(d, J=8 Hz, 1H)

Examples

Starting with10-methoxymethyl-8-chloromethyl-10H-pyrazino[2,3-b][1,4]benzothiazine,the following compounds were obtained by the same method as the one ofExample 1094.

Ex. Structural formula NMR 1097

¹H-NMR(DMSO-d₆) δ ppm: 3.33(s, 3H), 4.80(s, 2H), 5.19(s, 2H), 5.60(d,J=8.2Hz, 1H), 6.91(d, J=7.9Hz, 1H), 7.02(s, 1H), 7.11(d, J=7.9Hz, 1H),7.73(d, J=8.2Hz, 1H), 7.93(d, J=3.0Hz, 1H), 7.96(d, J=3.0Hz, 1H),11.34(br.s, 1H) 1098

¹H-NMR(DMSO-d₆) δ ppm: 3.30(s, 3H), 5.09(s, 2H), 5.31(s, 2H), 6.77(dd,J=1.7, 8.1Hz, 1H), 6.88(d, J=1.7Hz, 1H), 6.97(d, J=8.1Hz, 1H),7.25-7.33(m, 4H), 7.83(d, J=2.7Hz, 1H), 7.85(d, J=2.7Hz, 1H), 7.96(s,1H) 1099

¹H-NMR(DMSO-d₆) δ ppm: 3.23(s, 3H), 5.14(s, 2H), 5.49(s, 2H), 6.93(d,J=7.8Hz, 1H), 7.02(s, 1H), 7.09(d, J=7.8Hz, 1H), 7.24(dd, J=5.1, 8.1Hz,1H), 7.91(d, J=2.9Hz, 1H), 7.94(d, J=2.9Hz, 1H), 7.99(d, J=8.1Hz, 1H),8.40(d, J=5.1Hz, 1H), 8.64(s, 1H) 1100

¹H-NMR(DMSO-d₆) δ ppm: 3.23(s, 3H), 5.10(s, 2H), 5.44(s, 2H), 6.94(dd,J=1.2, 8.2Hz, 1H), 7.06(d, J=1.2Hz, 1H), 7.07(d, J=8.2Hz, 1H), 7.28(dd,J=4.9, 8.6Hz, 1H), 7.91(d, J=2.9Hz, 1H), 7.93(d, J=2.9Hz, 1H), 8.09(dd,J=1.2, 8.6Hz, 1H), 8.37(dd, J=1.2, 4.9Hz, 1H), 8.58(s, 1H) 1101

¹H-NMR(CDCl₃) δ ppm: 3.38(s, 3H), 5.13(s, 2H), 5.79(s, 2H), 6.85(dd,J=2, 8Hz, 1H), 6.97(d, J=8Hz, 1H), 6.99(d, J=2Hz, 1H), 7.35-7.47(m, 3H),7.82(d, J=3Hz, 1H), 7.84(d, J=3Hz, 1H), 8.08(dt, J=1, 8Hz, 1H) 1102

¹H-NMR(CDCl₃) δ ppm: 3.33(s, 3H), 5.12(s, 2H), 5.20(s, 2H), 6.84(dd,J=2, 8Hz, 1H), 6.93(d, J=8Hz, 1H), 6.96(d, J=2Hz, 1H), 7.10(t, J=8Hz,1H), 7.25(d, J=8Hz, 1H), 7.42(d, J=8Hz, 1H), 7.75(d, J=8Hz, 1H), 7.79(d,J=3Hz, 1H), 7.81(d, J=3Hz, 1H)

Examples

The following compounds were obtained by treating the compounds obtainedin Examples 1095 and 1097 by the same method as the one of Example 434.

Ex. Structural formula MS M.p. NMR 1103

210-212° C. ¹H-NMR(DMSO-d₆) δ ppm: 5.54(s, 2H), 6.62(d, J=1.9Hz, 1H),6.73(dd, J=1.9, 7.8Hz, 1H), 6.92(d, J=7.8Hz, 1H), 7.63(d, J=3.1Hz, 1H),7.64(d, J=3.1Hz, 1H), 9.48(s, 1H), 9.54(s, 1H) 1104

206-208° C. ¹H-NMR(DMSO-d₆) δ ppm: 5.78(s, 2H), 6.66(d, J=1.7Hz, 1H),6.77(dd, J=1.7, 7.8Hz, 1H), 6.91(d, J=7.8Hz, 1H), 7.63(d, J=3.1Hz, 1H),7.64(d, J=3.1Hz, 1H), 9.00(s, 1H), 9.55(s, 1H) 1105

269-271° C. ¹H-NMR(DMSO-d₆) δ ppm: 4.69(s, 2H), 5.60(d, J=8.4Hz, 1H),6.62(d, J=1.8Hz, 1H), 6.68(dd, J=1.8, 8.1Hz, 1H), 6.88(d, J=8.1Hz, 1H),7.63(s, 2H), 7.67(d, J=8.4Hz, 1H), 11.34(br.s, 1H)

Examples

The following compounds were obtained by treating methoxymethylcompounds by the same method as the one of Example 9.

Ex. Structural formula MS M.p. NMR 1106

ESI (+) 332 (MH⁺) 202-204° C. ¹H-NMR(DMSO-d₆) δ ppm: 5.28(s, 2H),6.50(d, J=4Hz, 1H), 6.60-6.63(m, 2H), 6.83(d, J=8Hz, 1H), 7.09(dd, J=5,8Hz, 1H), 7.55(d, J=4Hz, 1H), 7.61(s, 2H), 7.97(dd, J=1, 8Hz, 1H),8.23(dd, J=1, 5Hz, 1H), 9.48(s, 1H) 1107

FAB (+) 332 (MH⁺) 210-214° C. ¹H-NMR(DMSO-d₆) δ ppm: 5.73(s, 2H),6.66(s, 1H), 6.72(d, J=2Hz, 1H), 6.86(dd, J=2, 8Hz, 1H), 6.87(d, J=8Hz,1H), 7.11(dd, J=6, 7Hz, 1H), 7.60(d, J=3Hz, 1H), 7.61(d, J=3Hz, 1H),8.17(d, J=6Hz, 1H), 8.30(d, J=7Hz, 1H), 9.51(s, 1H) 1108

ESI (+) 282 (MH⁺) 211-212° C. ¹H-NMR(DMSO-d₆) δ ppm: 5.14(s, 2H),6.25(t, J=2.0Hz, 1H), 6.61(d, J=1.5Hz, 1H), 6.61(d, J=8.5Hz, 1H),6.84(dd, J=1.5, 8.5Hz, 1H), 7.44(d, J=2.0Hz, 1H), 7.62(s, 2H), 7.76(d,J=2.0Hz, 1H), 9.52(s, 1H) 1109

¹H-NMR(DMSO-d₆) δ ppm: 5.33(s, 2H), 6.60(s, 1H), 6.70(d, J=8.1Hz, 1H),6.87(d, J=8.1Hz, 1H), 7.14-7.23(m, 2H), 7.43(d, J=6.7Hz, 1H), 7.61(s,1H), 7.65(d, J=6.7Hz, 1H), 8.32(s, 1H), 9.46(s, 1H) 1110

FAB (+) 332 (M⁺) 251-258° C. ¹H-NMR(DMSO-d₆) δ ppm: 5.80(s, 2H), 6.63(d,J=2Hz, 1H), 6.67(dd, J=2, 8Hz, 1H), 6.88(d, J=8Hz, 1H), 7.40(ddd, J=1,7, 8Hz, 1H), 7.54(ddd, J=1, 7, 8Hz, 1H), 7.61(s, 2H), 7.79(td, J=1, 8Hz,1H), 8.25(td, J=1, 8Hz, 1H), 9.47(s, 1H) 1111

>275° C. ¹H-NMR(DMSO-d₆) δ ppm: 5.15(s, 2H), 6.61(s, 1H), 6.62(d, J=8Hz,1H), 6.81(d, J=8Hz, 1H), 6.98(t, J=8Hz, 1H), 7.31(t, J=8Hz, 1H), 7.43(d,J=8Hz, 1H), 7.60(s, 2H), 7.61(d, J=8Hz, 1H), 9.38(s, 1H) 1112

265° C. (decom- pose) ¹H-NMR(DMSO-d₆) δ ppm: 5.37(s, 2H), 6.57(t, J=1Hz,1H), 6.76(dd, J=1, 8Hz, 1H), 6.91(dd, J=1, 8Hz, 1H), 7.24(dd, J=5, 8Hz,1H), 7.61(m, 2H), 7.89(dd, J=2, 8Hz, 1H), 8.41(dd, J=2, 5Hz, 1H),8.58(s, 1H), 9.44(s, 1H) 1113

249-251° C. ¹H-NMR(DMSO-d₆) δ ppm: 5.36(s, 2H), 6.64(t, J=1Hz, 1H),6.73(dd, J=1, 8Hz, 1H), 6.87(dd, J=1, 8Hz, 1H), 7.29(dd, J=5, 8Hz, 1H),7.61(m, 2H), 8.10(dd, J=2, 8Hz, 1H), 8.35(dd, J=2, 5Hz, 1H), 8.54(s,1H), 9.47(s, 1H)

Examples

The following compounds were obtained by treating10-methoxymethyl-8-chloromethyl-10H-pyrazino[2,3-b][1,4]-benzothiazinesuccessively by the same methods as those of Examples 1094 and 434.

Ex. Structural formula MS M.p. NMR 1114

197-198° C. ¹H-NMR(DMSO-d₆) δ ppm: 4.919s, 2H), 6.00(t, J=2.0Hz, 2H),6.55(d, J=7.9Hz, 1H), 6.58(s, 1H), 6.73(t, J=2.0Hz, 2H), 6.86(d,J=7.9Hz, 1H), 7.62(s, 2H), 9.52(s, 1H) 1115

223-226° C. ¹H-NMR(DMSO-d₆) δ ppm: 5.23(s, 2H), 6.60(d, J=1.6Hz, 1H),6.67(dd, J=1.6, 7.8Hz, 1H), 6.88(d, J=7.8Hz, 1H), 7.62(s, 2H), 7.98(s,1H), 8.61(s, 1H), 9.53(s, 1H)

Example 111610-Methoxymethyl-8-(thiazol-2-ylmethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine

150 mg of the title compound was obtained as a yellow oily substance bytreating 380 mg of(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)thioacetamidewith chloroacetaldehyde by the same method as the one of Example 1125.

¹H-NMR(CDCl₃) δ ppm: 3.49(s, 3H), 4.29(s, 2H), 5.25(s, 2H), 6.91(dd,J=1.6, 7.9 Hz, 1H), 6.98(d, J=7.9 Hz, 1H), 7.09(dd, J=1.6 Hz, 1H),7.24(d, J=3.3 Hz, 1H), 7.72(d, J=3.3 Hz, 1H), 7.84(s, 2H)

Example 1117O-[[10-(Methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl]-[1-(N,N-dimethylsulfamoyl)imidazol-2-yl]methyl]O-phenylthiocarbonate

Into a solution of 0.317 g ofN,N-dimethyl-2-[[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-hydroxymethyl]]imidazole-1-sulfonamideand 0.117 g of 4-dimethylaminopyridine in acetonitrile (15 ml) wasdropped in a nitrogen atmosphere at 0° C. a solution of 0.146 g ofphenyl chlorothioformate in acetonitrile (1 ml) and the resultingmixture was stirred at room temperature for 16 hours. Then the reactionmixture was distilled off under reduced pressure and the residue waspurified by silica gel column chromatography (eluted withdichloromethane/methanol) to thereby give 0.202 g of the title compoundas a yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 2.78(s, 6H), 3.48(s, 3H), 5.17(d, J=10Hz, 1H),5.22(d, J=10 Hz, 1H), 6.96(d, J=8 Hz, 1H), 7.10-7.41(m, 10H), 7.82(s,2H)

Example 1118N,N-Dimethyl-[2-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl]methyl]imidazol-1-ylsulfonamide

To a solution of 0.202 g of0-[[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl]-[1-(N,N-dimethyl-sulfamoyl)imidazol-2-yl]methyl]O-phenylthiocarbonate in toluene (15 ml) were added 0.20 ml of tri-n-butyltinhydride and 0.02 g of a,a′-azobis(isobutyronitrile). After degassing,the reaction mixture was heated to 75° C. in a nitrogen atmosphere for 3hours. After further adding 0.10 ml of tri-n-butyltin hydride, thereaction mixture was heated for 2 hours. After distilling off thesolvent under-reduced pressure completely, the residue was purified bysilica gel column chromatography (eluted with dichloromethane/methanol)to thereby give 0.064 g of the title compound as a yellow solid.

¹H-NMR(CDCl₃) δ ppm: 2.75(s, 6H), 3.47(s, 3H), 4.38(s, 2H), 5.21(s, 2H),6.89(dd, J=2, 8 Hz, 1H), 6.94(d, J=8 Hz, 1H), 7.02(d, J=2 Hz, 1H),7.03(d, J=2 Hz, 1H), 7.24(d, J=2 Hz, 1H), 7.82(d, J=2 Hz, 1H), 7.83(d,J=2 Hz, 1H)

Example 111910-(Methoxymethyl)-8-(imidazol-2-ylmethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine

To 0.064 g ofN,N-dimethyl-[2-110-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl]methyl]imidazol-1-yl]sulfonamidewas added 5 ml of a 10% aqueous solution of sodium hydroxide. Afterdegassing, the resulting mixture was heated under reflux in a nitrogenatmosphere for 14 hours. After distilling off the solvent under reducedpressure completely, the residue was purified by silica gel columnchromatography (eluted with dichloromethane/methanol) to thereby give0.020 g of the title compound as a yellow solid.

¹H-NMR(CDCl₃) δ ppm: 3.47(s, 3H), 4.03(s, 2H), 5.20(s, 2H), 6.81(d, J=8Hz, 1H), 6.92-6.97(m, 4H), 7.82(d, J=3 Hz, 1H), 7.83(d, J=3 Hz, 1H)

Example 11208-[2-(Pyridin-4-yl)ethyl]-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine

Similar to Production Example 14, 0.82 g of(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbaldehydewas treated with (pyridin-4-ylmethyl)triphenylphosphonium bromide in thepresence of tert-butoxypotassium to thereby give 1.10 g of8-[2-(pyridin-4-yl)vinyl]-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazineas yellow crystals. Subsequently, the obtained product was hydrogenatedin a solvent mixture of ethanol (20 ml) with tetrahydrofuran (20 ml) inthe presence of 0.2 g of 10% palladium-carbon (moisture content: 50%) atroom temperature under atmospheric pressure for 5 hours to thereby give1.00 g of the title compound as yellow crystals.

¹H-NMR(CDCl₃) δ ppm: 2.98(s, 4H), 3.47(s, 3H), 5.19(s, 2H), 6.75(d, J=8Hz, 1H), 6.87(s, 1H), 6.92(d, J=8 Hz, 1H), 7.54(d, J=8 Hz, 2H), 7.81(d,J=3 Hz, 1H), 7.83(d, J=3 Hz, 1H), 8.48(d, J=8 Hz, 2H)

Example 11218-(Thiazol-2-ylmethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine

The title compound was obtained by treating10-methoxymethyl-8-(thiazol-2-ylmethyl)-10H-pyrazinol2,3-b][1,4]benzothiazineby the same method as the one of Example 434.

¹H-NMR(CDCl₃) δ ppm: 4.18(s, 2H), 6.45(d, J=1.7 Hz, 1H), 6.52(br.s, 1H),6.79(dd, J=1.7, 8.0 Hz, 1H), 6.86(d, J=8.0 Hz, 1H), 7.24(d, J=3.3 Hz,1H), 7.56(d, J=2.9 Hz, 1H), 7.69(d, J=2.9 Hz, 1H), 7.72(d, J=3.3 Hz, 1H)

MS: ESI(+)298(M⁺)

m.p.: 160-161° C.

Example 11228-(Imidazol-2-ylmethyl)-10H-pyrazino(2,3-b][1,4]benzothiazine

The title compound was obtained as a yellow amorphous product bytreating10-(methoxymethyl)-8-(imidazol-2-ylmethyl)-10H-pyrazino[2,3-b][1,4]benzothiazineby the same method as the one of Example 9.

¹H-NMR(CD₃OD) δ ppm: 3.96(s, 2H), 6.54(s, 1H), 6.68(d, J=8 Hz, 1H),6.81(d, J=8 Hz, 1H), 7.01-7.18(br.s, 2H), 7.55(d, J=3 Hz, 1H), 7.56(d,J=3 Hz, 1H)

MS: FAB(+)262(MH⁺)

Examples

The following compounds were obtained by treating8-[2-(pyridin-4-yl)vinyl]-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazineand8-[2-(pyridin-4-yl)ethyl]-10-methoxymethyl-1H-pyrazino[2,3-b][1,4]benzothiazineby the same method as the one of Example 8.

Ex. Structural formula MS M.p. NMR 1123

ESI(+) 305 (MH⁺) >275° C. ¹H-NMR(DMSO-d₆) δ pm: 6.99(d, J=1Hz, 1H),7.02(d, J=8Hz, 1H), 7.19(dd, J=1, 8Hz, 1H), 7.28(d, J=16Hz, 1H), 7.64(d,J=3Hz, 1H), 7.66(d, J=3Hz, 1H), 7.77(d, J=16Hz, 1H), 8.14(d, J=7Hz, 2H),8.79(d, J=7Hz, 2H), 9.65(s, 1H) 1124

ESI(+) 307 (MH⁺) 179-183° C. ¹H-NMR(DMSO-d₆) δ ppm: 2.62(t, J=8Hz, 2H),2.82(t, J=8Hz, 2H), 6.59(d, J=2Hz, 1H), 6.75(dd, J=2, 8Hz, 1H), 6.80(d,J=8Hz, 1H), 7.22(d, J=5Hz, 2H), 7.62(d, J=3Hz, 1H), 7.63(d, J=3Hz, 1H),8.43(d, J=5Hz, 2H), 9.43(s, 1H)

Example 11258-[4-(2-Pyridyl)thiazol-2-ylmethyl]-10H-pyrazino[2,3-b][1,4]benzothiazine

To a solution of 550 mg of(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)thioacetamide in a solventmixture of ethanol (10 ml) with N,N-dimethylformamide (10 ml) was added560 mg of (2-bromoacetyl)pyridine hydrobromide and the resulting mixturewas heated to 60 to 70° C. for 2 hours. Then the reaction mixture wasbrought back to room temperature and distributed into dichloromethaneand an aqueous solution of sodium bicarbonate. After extracting theorganic layer, the extract was washed with water and dried overanhydrous sodium sulfate. After distilling off the solvent under reducedpressure, the crystals thus precipitated were washed successively withethyl acetate and diethyl ether to thereby give 420 mg of the titlecompound as yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 4.21(s, 2H), 6.77(s, 1H), 6.81(d, J=8.6 Hz, 1H),6.89(d, J=8.6 Hz, 1H), 7.33(dd, J=5.4, 7.4 Hz, 1H), 7.62(s, 2H), 7.88(t,J=7.4 Hz, 1H), 8.05(d, J=7.4 Hz, 1H), 8.14(s, 1H), 8.59(d, J=5.4 Hz,1H), 9.52(s, 1H)

m.p.: 194-195° C.

Example 11268-(1,2,4-Triazol-3-ylmethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine

330 mg ofN-formyl-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetamidrazone wasdissolved in N,N-dimethylformamide (5 ml) and heated to 120° C. for 2hours. Then the reaction mixture was brought back to room temperature.After distilling off the solvent under reduced pressure, the obtainedresidue was crystallized from ethyl acetate/diethyl ether to therebygive 287 mg of the title compound as yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 3.79 and 3.78(br.s, 2H), 6.59-6.69(m, 2H),6.87-6.88(m, 1H), 7.62(s, 2H), 7.83 and 8.42(br.s, 1H), 9.42-9.51(br.s,1H), 13.37(br.s, 1H)

MS: FAB(+)282(M⁺)

Example 11278-(6-Methyl-1,4-dihydro-1,2,4,5-tetrazin-3-yl)-10H-pyrazino-[2,3-b][1,4]benzothiazine

To a solution of 0.274 g of(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)thioacetamide intetrahydrofuran (40 ml) was added 0.1 ml of hydrazine monohydrate andthe resulting mixture was stirred for 30 minutes. After further adding1.0 ml of hydrazine monohydrate, the mixture was stirred for additional1 hour. After distilling off the solvent under reduced pressure, theresidue was dissolved in ethanol (40 ml) and tetrahydrofuran (20 ml).After adding 5 ml of triethyl orthoacetate, the resulting mixture washeated under reflux for 4 hours. Then the reaction mixture wasdistilled.off under reduced pressure and the residue was purified bysilica gel column chromatography (eluted with dichloromethane/methanol)to thereby give 50 mg of the title compound as a pale yellow solid.

¹H-NMR(DMSO-d₆) δ ppm: 1.65(s, 3H), 3.12(s, 2H), 6.65(d, J=1 Hz, 1H),6.70(dd, J=1, 8 Hz, IH), 6.83(d, J=8 Hz, 1H), 7.63(d, J=3 Hz, 1H),7.64(d, J=3 Hz, 1H), 7.76(s, 1H), 7.83(s, 1H), 9.50(s, 1H)

MS: FAB(+)311(MH⁺)

m.p.: 233-235° C.

Example 1128(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-(pyridin-3-yl)methanol

Into a solution of 0.45 ml of 3-bromopyridine in dry ether (20 ml) wasdropped in a nitrogen atmosphere at −78° C. 3.2 ml of a 1.6 M solutionof n-butyllithium in hexane and the resulting mixture was stirred for 30minutes. Then 5 ml of a solution of 450 mg of(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbaldehydein dry tetrahydrofuran was dropped into the reaction mixture and theresulting mixture was stirred at −45 to −20° C. for 1 hour. After addingwater carefully, the reaction mixture was extracted with ethyl acetate.The extract was washed with water, dried over anhydrous sodium sulfateand filtered. After distilling off the solvent under reduced pressure,the reside was purified by silica gel column chromatography (eluted withdichloromethane/methanol) to thereby give 500 mg of the title compoundas a yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 2.80-2.93(br.s, 1H), 3.48(s, 3H), 5.22(s, 2H),5.80(s, 1H), 6.94(br.d, J=8.2 Hz, 1H), 6.99(br.d, J=8.2 Hz, 1H), 7.15(s,1H), 7.27(dd, J=4.9, 8.2 Hz, 1H), 7.68(br.d, J=8.2 Hz, 1H), 7.83(d,J=3.1 Hz, 1H), 7.84(d, J=3.1 Hz, 1H), 8.50(d, J=4.9 Hz, 1H), 8.61(br.s,1H)

Examples

Similar to Example 1128, aromatic halides were reacted with(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbaldehydeto thereby give the following compounds. Two compounds were obtained bytreating 1-bromo-2,4-difluorobenzene with n-butyllithium and thenreacting with(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbaldehyde.

Ex. Structural formula NMR 1129

¹H-NMR(CDCl₃) δ ppm: 3.46(s, 3H), 5.20- 5.40(br.s, 1H), 5.22(s, 2H),5.41(s, 1H), 6.96(s, 2H), 7.15(s, 1H), 7.18(d, J=7.8Hz, 1H), 7.20(dd,J=4.8, 7.8Hz, 1H), 7.63(dt, J=1.5, 7.8Hz, 1H), 7.81(s, 2H), 8.54(d,J=1.5, 4.8Hz, 1H) 1130

¹H-NMR(CDCl₃) δ ppm: 3.49(s, 3H), 4.40(d, J=6Hz, 1H), 5.25(s, 2H),5.80(d, J=6Hz, 1H), 6.97(dd, J=2, 8Hz, 1H), 6.99(d, J=8Hz, 1H), 7.20(d,J=2Hz, 1H), 7.82(d, J=3Hz, 1H), 7.83(d, J=3Hz, 1H), 8.51(d, J=3Hz, 1H),8.52(dd, J=2, 3Hz, 1H), 8.61(d, J=2Hz, 1H) 1131

¹H-NMR(CDCl₃) δ ppm: 3.35(s, 3H), 5.24(s, 2H), 5.78(d, J=4Hz, 1H),6.34(d, J=4Hz, 1H), 7.03(dd, J=2, 8Hz, 1H), 7.08(d, J=8Hz, 1H), 7.20(d,J=2Hz, 1H), 7.93(d, J=3Hz, 1H), 7.96(d, J=3Hz, 1H), 8.77(s, 2H), 9.07(s,1H) 1132

¹H-NMR(CDCl₃) δ ppm: 2.52(s, 1H), 3.48(s, 3H), 5.23(s, 2H), 5.77(s, 1H),6.91(dd, J=2, 8Hz, 1H), 6.99(d, J=8Hz, 1H), 7.13(d, J=2Hz, 1H), 7.42(d,J=8Hz, 1H), 7.53(dd, J=2, 8Hz, 1H), 7.83(d, J=3Hz, 1H), 7.84(d, J=3Hz,1H), 8.40(d, J=2Hz, 1H) 1133

¹H-NMR(CDCl₃) δ ppm: 2.76(br.s, 1H), 3.43(s, 3H), 5.18(d, J=9.0Hz, 1H),5.22(d, J=9.0Hz, 1H), 5.72(br.s, 1H), 6.92(d, J=7.8Hz, 1H), 6.94(d,J=7.8Hz, 1H), 7.13(s, 1H), 7.23- 7.29(m, 1H), 7.30- 7.37(m, 4H), 7.79(d,J=2.9Hz, 1H), 7.81(d, J=2.9Hz, 1H) 1134

¹H-NMR(CDCl₃) δ ppm: 2.73(d, J=8Hz, 1H), 3.47(s, 3H), 5.21(d, J=9Hz,1H), 5.24(d, J=9Hz, 1H), 6.17(d, J=8Hz, 1H), 6.86(dt, J=3, 9Hz, 1H),6.86(br.d, J=8Hz, 1H), 6.99(d, J=8Hz, 1H), 7.20(br.s, 1H), 7.49(ddd,J=6, 8, 9Hz, 1H), 7.84(m, 2H) 1135

¹H-NMR(CDCl₃) δ ppm: 2.78(d, J=9Hz, 1H), 3.44(s, 3H), 5.21(s, 2H),6.16(d, J=9Hz, 1H), 6.90-6.94(m, 2H), 6.95-7.00(m, 2H), 7.20(s, 1H),7.24- 7.31(m, 1H), 7.84(s, 2H) 1136

¹H-NMR(CDCl₃) δ ppm: 2.57(d, J=6Hz, 1H), 3.48(s, 3H), 5.19(d, J=9Hz,1H), 5.22(d, J=9Hz, 1H), 6.019d, J=6Hz, 1H), 6.90(t, J=9Hz, 1H), 6.96(m,2H), 7.14(s, 1H), 7.36(ddd, J=3, 5, 9Hz, 1H), 7.69(dd, J=3, 6Hz, 1H),7.83(s, 2H)

Example 1137(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-[1-(triphenylmethyl)imidazol-2-yl]methanol

50 ml of a solution of 1.32 g of 1-(triphenylmethyl)imidazole in drytetrahydrofuran was ice-cooled in a nitrogen atmosphere. After adding2.8 ml of a 1.6 M solution of n-butyllithium in hexane, the resultingmixture was stirred for 2 hours. Then the reaction mixture was cooled to−78° C. After adding 1.23 g of cerium (III) chloride, the reactionmixture was stirred for 30 minutes. Further, 40 ml of a solution of0.546 g of(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbaldehydein dry tetrahydrofuran was dropped thereinto. Then the reaction mixturewas brought back to room temperature and distributed into an aqueoussolution of sodium dihydrogenphosphate and ethyl acetate. Afterfiltering off the inorganic matters, the aqueous layer was extractedwith ethyl acetate, washed successively with water and a saturatedaqueous solution of sodium chloride and dried over anhydrous sodiumsulfate followed by filtration. After distilling off the solvent underreduced pressure, the residue was purified by silica gel columnchromatography (eluted with dichloromethane/methanol) to thereby give716 mg of the title compound as a yellow solid.

¹H-NMR(CDCl₃) δ ppm: 2.84(d, J=8 Hz, 1H), 3.44(s, 3H), 4.98(d, J=8 Hz,1H), 5.07(d, J=9 Hz, 1H), 5.19(d, J=9 Hz, 1H), 6.40(dd, J=2, 8 Hz, 1H),6.68(d, J=8 Hz, 1H), 6.77(d, J=2 Hz, 1H), 6.78(d, J=2 Hz, 1H),7.09-7.12(m, 7H), 7.23-7.26(m, 9H), 7.82(s, 2H)

Examples

The following compounds were obtained by starting with(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbaldehydeand each of 1-bromo-4-fluorobenzene, 4-bromoanisole and 2-bromothiazole.

Ex. Structural formula NMR 1138

¹H-NMR(CDCl₃) δ ppm: 2.23(s, 1H), 3.46(s, 3H), 5.21(d, J=9Hz, 1H),5.24(d, J=9Hz, 1H), 5.76(s, 1H), 6.95(dd, J=2, 8Hz, 1H), 6.98(d, J=8Hz,1H), 7.039t, J=9Hz, 2H), 7.12(d, J=2Hz, 1H), 7.34(dd, J=5, 9Hz, 2H),7.83(d, J=3Hz, 1H), 7.84(d, J=3Hz, 1H) 1139

¹H-NMR(CDCl₃) δ ppm: 3.53(s, 3H), 3.78(s, 3H), 4.63(s, 1H), 5.29(s, 1H),5.32(s, 2H), 6.78(d, J=8Hz, 2H), 7.08(d, J=8Hz, 1H), 7.15(d, J=8Hz, 1H),7.16(s, 1H), 7.36(d, J=8Hz, 2H), 7.87(s, 2H) 1140

¹H-NMR(CDCl₃) δ ppm: 3.44(s, 1H), 3.509s, 3H), 5.26(s, 2H), 6.01(s, 1H),7.02(d, J=8Hz, 1H), 7.18(dd, J=2, 8Hz, 1H), 7.26(d, J=2Hz, 1H), 7.33(d,J=3Hz, 1H), 7.75(d, J=3Hz, 1H), 7.83(d, J=3Hz, 1H), 7.84(d, J=3Hz, 1H)

Example 1141(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-(pyrimidin-2-yl)methanol

10 ml of a solution of 1.85 g of 2-(tributylstannyl)pyrimidine intetrahydrofuran was cooled to −75° C. in a nitrogen atmosphere. Then 3.1ml of a 1.6 M solution of n-butyllithium in hexane was droppedthereinto. After stirring for 10 minutes, 1.23 g of cerium (III)chloride was added thereto and the reaction mixture was stirred for 30minutes. Further, 40 ml of a solution of 0.54 g of(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbaldehydein tetrahydrofuran was dropped thereinto. After stirring at −75° C. for30 minutes, the reaction mixture was brought back to room temperatureand distributed into water and ethyl acetate. After filtering off theinorganic matters, the aqueous layer was extracted with ethyl acetate,washed successively with water and a saturated aqueous solution ofsodium chloride and dried over anhydrous sodium sulfate followed byfiltration. After distilling off the solvent under reduced pressure, theresidue was purified by silica gel column chromatography (eluted withdichloromethane/methanol) to thereby give 532 mg of the title compoundas a yellow solid.

¹H-NMR(CDCl₃) δ ppm: 3.52(s, 3H), 4.98(d, J=6 Hz, 1H), 5.25(d, J=10 Hz,1H), 5.29(d, J=10 Hz, 1H), 5.80(d, J=6 Hz, 1H), 6.97(d, J=8 Hz, 1H),7.11(d, J=8 Hz, 1H), 7.23(t, J=5 Hz, 1H), 7.30(s, 1H), 7.81(s, 2H),8.73(d, J=5 Hz, 2H)

Example 1142(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-(pyridin-4-yl)methanol

A solution of 609 mg of phenyl (pyridin-4-yl) sulfoxide intetrahydrofuran was cooled to −150° C. in a nitrogen atmosphere. Then1.5 ml of a 2 M solution of phenylmagnesium bromide in tetrahydrofuranwas dropped thereinto. After stirring at room temperature for 10minutes, 3 ml of a solution of 819 mg of(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbaldehydein tetrahydrofuran was dropped into the reaction mixture. After stirringfor 10 minutes, the reaction mixture was distributed into water andethyl acetate. Then the organic layer was extracted, washed with waterand dried over anhydrous sodium sulfate followed by filtration. Afterdistilling off the solvent under reduced pressure, the residue waspurified by silica gel column chromatography (eluted withdichloromethane/methanol) and recrystallized from ethyl acetate/n-hexaneto thereby give 260 mg of the title compound as yellow crystals.

¹H-NMR(CDCl₃) δ ppm: 3.45(s, 3H), 3.58-3.78(br.s, 1H), 5.20(s, 2H),5.70(s, 1H), 6.91(dd, J=1.5, 8.6 Hz, 1H), 6.96(d, J=8.6 Hz, 1H), 7.15(d,J=1.5 Hz, 1H), 7.31(d, J=6.4 Hz, 2H), 7.83(s, 2H), 8.49(d, J=6.4 Hz, 2H)

Example 1143(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-(imidazo[1,2-a]pyridin-5-yl)methanol

To 40 ml of a tetrahydrofuran solution were added 1.20 g of magnesiumand 0.1 ml of 1,2-dibromoethane in a nitrogen atmosphere. Subsequently,10 ml of a solution of 2.96 g of 5-bromoimidazo[1,2-a]pyridine and 2.8ml of 1,2-dibromoethane in tetrahydrofuran were dropped into thereaction mixture while heating under reflux. Further, 10 ml of asolution of 2.73 g of(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbaldehydein tetrahydrofuran was dropped thereinto. After heating to 50° C. for 1hour, the reaction mixture was brought back to room temperature anddistributed into an aqueous solution of ammonium chloride and ethylacetate. The organic layer was extracted, washed with water and driedover anhydrous sodium sulfate followed by filtration. After distillingoff the solvent under reduced pressure, the residue was purified bysilica gel column chromatography (eluted with dichloromethane/methanol)to thereby give 260 mg of the title compound as a yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 3.45(s, 3H), 3.60-3.85(br.s, 1H), 5.23(s, 2H),5.74(s, 1H), 6.95(dd, J=1.4, 7.7 Hz, 1H), 6.99(d, J=7.7 Hz, 1H),7.02(dd, J=1.7, 9.4 Hz, 1H), 7.19(d, J=1.4 Hz, 1H), 7.44(d, J=9.4 Hz,1H), 7.52(s, 1H), 7.57(d, J=1.7 Hz, 1H), 7.83(d, J=2.6 Hz, 1H), 7.85(d,J=2.6 Hz, 1H), 8.14(s, 1H)

Examples

The following compounds were obtained by the same method as the one ofExample 9.

Ex. Structural formula MS M.p. NMR 1144

¹H-NMR(CDCl₃) δ ppm: 5.20-5.40(br.s, 1H), 6.50(s, 1H), 6.78- 6.83(br.s,1H), 6.85(s, 2H), 7.18(d, J=7.8Hz, 1H), 7.23(dd, J=5.2, 7.8Hz, 1H),7.52(d, J=2.6Hz, 1H), 7.66(d, J=2.6Hz, 1H), 7.66(dt, J=1.6, 7.8Hz, 1H),8.55(dd, J=1.6, 5.2Hz, 1H) 1145

¹H-NMR(DMSO-d₆) δ ppm: 5.79(s, 1H), 6.80(d, J=7.7Hz, 1H), 6.82(s, 1H),6.89(d, J=7.7Hz, 1H), 7.62(s, 2H), 7.94(dd, J=5.2, 8.6Hz, 1H), 8.35(d,J=8.6Hz, 1H), 8.77(d, J=5.2Hz, 1H), 8.82(s, 1H), 9.49(s, 1H) 1146

¹H-NMR(DMSO-d₆) δ ppm: 5.51(d, J=4.0Hz, 1H), 6.11(d, J=4.0Hz, 1H),6.78(d, J=7.6Hz, 1H), 6.79(s, 1H), 6.84(d, J=7.6Hz, 1H), 7.31(d,J=5.8Hz, 2H), 7.61(s, 2H), 8.48(d, J=5.8Hz, 2H), 9.43(s, 1H) 1147

ESI(+) 310 (MH⁺) 218-221° C. ¹H-NMR(DMSO-d₆) δ ppm: 5.65(d, J=4Hz, 1H),6.26(d, J=4Hz, 1H), 6.80(d, J=8Hz, 1H), 6.83(s, 1H), 6.87(d, J=8Hz, 1H),7.63(s, 2H), 8.73(s, 2H), 9.07(s, 1H), 9.45(s, 1H) 1148

FAB(+) 310 (MH⁺) 105-107° C. ¹H-NMR(DMSO-d₆) δ ppm: 5.65(d, J=5Hz, 1H),6.25(d, J=5Hz, 1H), 6.80(d, J=8Hz, 1H), 6.82(s, 1H), 6.86(d, J=8Hz, 1H),7.64(s, 2H), 8.72(s, 2H), 9.06(s, 1H), 9.45(s, 1H) 1149

¹H-NMR(CDCl₃) δ ppm: 4.64(d, J=4Hz, 1H), 5.78(br.s, 1H), 6.55(br.s, 2H),6.85(dd, J=1, 8Hz, 1H), 6.88(d, J=8Hz, 1H), 7.55(d, J=3Hz, 1H), 7.68(d,J=3Hz, 1H), 8.52(s, 2H), 8.60(s, 1H) 1150

FAB(+) 314(M⁺) 110-114° C. ¹H-NMR(CDCl₃) δ ppm: 3.48(s, 1H), 5.95(s,1H), 6.59(d, J=1Hz, 1H), 6.82(d, J=8Hz, 1H), 6.91(dd, J=1, 8Hz, 1H),7.13(s, 1H), 7.31(d, J=4Hz, 1H), 7.50(d, J=3Hz, 1H), 7.64(d, J=3Hz, 1H),7.70(d, J=4Hz, 1H) 1151

ESI(+) 298(MH⁺) ¹H-NMR(DMSO-d₆) δ ppm: 5.52(d, J=6Hz, 1H), 6.14(d,J=6Hz, 1H), 6.77(d, J=8Hz, 1H), 6.82(s, 1H), 6.83(d, J=8Hz, 1H),6.87(br.s, 2H), 7.62(d, J=3Hz, 1H), 7.3(d, J=3Hz, 1H), 9.51(s, 1H) 1152

¹H-NMR(DMSO-d₆) δ ppm: 5.53(d, J=4.3Hz, 1H), 6.08(d, J=4.3Hz, 1H),6.71(d, J=7.7Hz, 1H), 6.72(s, 1H), 6.86(d, J=7.7Hz, 1H), 7.01(dd, J=1.3,9.0Hz, 1H), 7.46(d, J=9.0Hz, 1H), 7.52(s, 1H), 7.61(s, 2H), 7.95(s, 1H),8.50(d, J=1.3Hz, 1H), 9.44(s, 1H) 1153

¹H-NMR(CDCl₃) δ ppm: 2.38-2.50(br.s, 1H), 5.68(br.s, 1H), 6.54(s, 1H),6.66-6.72(br.s, 1H), 6.82(d, J=8.6Hz, 1H), 6.83(d, J=8.6Hz, 1H),7.27-7.32(m, 2H), 7.32- 7.38(m, 2H), 7.49(d, J=2.9Hz, 1H), 7.65(d,J=2.9Hz, 1H) 1154

FAB(+) 325 (MH⁺) 150-152° C. ¹H-NMR(DMSO-d₆) δ ppm: 5.51(d, J=4Hz, 1H),5.93(d, J=4Hz, 1H), 6.74(dd, J=1, 8Hz, 1H), 6.80(d, J=1Hz, 1H), 6.82(d,J=8Hz, 1H), 7.12(t, J=9Hz, 2H), 7.33(dd, J=6, 9Hz, 2H), 7.61(d, J=3Hz,1H), 7.62(d, J=3Hz, 1H), 9.44(s, 1H) 1155

FAB(+) 405(M⁺) 202-203° C. ¹H-NMR(CDCl₃) δ ppm: 5.94(s, 1H), 6.50(br.s,1H), 6.55(d, J=1Hz,1H), 6.84(dd, J=1, 8Hz, 1H), 6.87(d, J=8Hz, 1H),6.92(t, J=9Hz, 1H), 7.38(ddd, J=3, 5, 9Hz, 1H), 7.40(dd, J=3, 6Hz, 1H),7.55(d, J=3Hz, 1H), 7.69(d, J=3Hz, 1H) 1156

FAB(+) 387(M⁺) 175-176° C. ¹H-NMR(DMSO-d₆) δ ppm: 5.90(s, 1H),6.15(br.s, 1H), 6.71(d, J=8Hz, 1H), 6.83(d, J=8Hz, 1H), 6.88(s, 1H),7.04(br.t, J=9Hz, 2H), 7.36(tt, J=7, 9Hz, 1H), 7.62(s, 2H), 9.45(s, 1H)1157

FAB(+) 467(M⁺) 198-200° C. ¹H-NMR(CDCl₃) δ ppm: 6.09(s, 1H), 6.60(br.s,1H), 6.61(s, 1H), 6.79(d, J=8Hz, 1H), 6.85(d, J=8Hz, 1H), 6.88(td, J=8,11Hz, 1H), 7.51(ddd, J=5, 7, 8Hz, 1H), 7.65(d, J=3Hz, 1H), 7.69(d,J=3Hz, 1H) 1158

FAB(+) 337(M⁺) 84-86° C. ¹H-NMR(CDCl₃) δ ppm: 3.79(s, 3H), 5.43(s, 1H),6.54(d, J=1Hz, 1H), 6.66(br.s, 1H), 6.81(dd, J=1, 8Hz, 1H), 6.84(d,J=8Hz, 1H), 6.88(d, J=9Hz, 2H), 7.25(d, J=9Hz, 2H), 7.50(d, J=3Hz, 1H),7.66(d, J=3Hz, 1H)

Example 1159(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-yl)-(2-bromopyridin-5-yl)methanol

The title compound was obtained by treating(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-(2-bromopyridin-5-yl)methanol by the samemethod as the one of Example 434.

¹H-NMR(DMSO-d₆) δ ppm: 5.50(s, 1H), 6.20(br.s, 1H), 6.77(d, J=8 Hz, 1H),6.78(s, 1H), 6.85(d, J=8 Hz, 1H), 7.60(d, J=8 Hz, 1H), 7.61(d, J=8 Hz,1H), 7.62(d, J=3 Hz, 1H), 7.63(d, J=3 Hz, 1H), 8.36(s, 1H), 9.45(s, 1H)

MS: FAB(+)388(M⁺)

m.p.: 221-223° C.

Example 1160(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)(pyridin-3-yl)ketone

1.25 g of the title compound was obtained by oxidizing 1.48 g of(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-(pyridin-3-yl)methanolwith manganese dioxide by the same method as the one of Example 625.

¹H-NMR(CDCl₃) δ ppm: 3.48(s, 3H), 5.29(s, 2H), 7.13(d, J=8 Hz, 1H),7.36(dd, J=2, 8 Hz, 1H), 7.45(ddd, J=1, 5, 8 Hz, 1H), 7.58(d, J=2 Hz,1H), 7.88(d, J=3 Hz, 1H), 7.89(d, J=3 Hz, 1H), 8.10(td, J=2, 8 Hz, 1H),8.82(dd, J=2, 5 Hz, 1H), 8.99(dd, J=1, 2 Hz, 1H)

Example 11618-[(Pyridin-3-yl)difluoromethyl]-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine

350 mg of(10-methoxymethyl-1H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)(pyridin-3-yl)ketonewas added in a nitrogen atmosphere to 3 ml of dimethylaminosulfurtrifluoride and the resulting mixture was stirred at room temperaturefor 16 hours and then at 50° C. for additional 5 hours. The reactionmixture was ice-cooled and diluted with ethyl acetate. After addingwater under ice-cooling, the extract was dried over anhydrous magnesiumsulfate and filtered. After distilling off the solvent under reducedpressure, the residue was purified by silica gel column chromatography(eluted with dichloromethane/ethyl acetate) to thereby give 287 mg ofthe title compound as a yellow solid.

¹H-NMR(CDCl₃) δ ppm: 3.48(s, 3H), 5.24(s, 2H), 7.06(s, 2H), 7.25(s, 1H),7.37(dd, J=5, 8 Hz, 1H), 7.80(d, J=8 Hz, 1H), 7.86(d, J=3 Hz, 1H),7.87(d, J=3 Hz, 1H), 8.70(d, J=5 Hz, 1H), 8.77(s, 1H)

Example 11628-[(Pyridin-3-yl)fluoromethyl]-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine

177 mg of the title compound was obtained by treating 352 mg of(10-methoxymethyl10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-(pyridin-3-yl)methanolby the same method as the one of Example 1161.

¹H-NMR(CDCl₃) δ ppm: 3.46(s, 3H), 5.21(d, J=9 Hz, 1H), 5.24(d, J=9 Hz,1H), 6.44(d, J=45 Hz, 1H), 6.91(d, J=8 Hz, 1H), 7.04(d, J=8 Hz, 1H),7.11(s, 1H), 7.32(dd, J=5, 8 Hz, 1H), 7.64(d, J=8 Hz, 1H), 7.83-7.85(m,2H), 8.60-8.63(m, 2H)

Example 11638-[1-(Pyridin-3-yl)-1-methoxymethyl]-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine

504 mg of the title compound was obtained as yellow crystals by treating704 mg of(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]-benzothiazin-8-yl)-(pyridin-3-yl)methanolwith methyl iodide in the. presence of sodium hydride by the same methodas the one of Example 788.

¹H-NMR(CDCl₃) δ ppm: 3.48(s, 3H), 3.48(s, 3H), 5.20(s, 1H), 5.22(d, J=10Hz, 1H), 5.25(d, J=10 Hz, 1H), 6.94(dd, J=2, 8 Hz, 1H), 7.00(d, J=8 Hz,1H), 7.11(d, J=2 Hz, 1H), 7.26(dd, J=5, 8 Hz, 1H), 7.63(td, J=2, 8 Hz,1H), 7.83(d, J=3 Hz, 1H), 7.84(d, J=3 Hz, 1H), 8.52(dd, J=2, 5 Hz, 1H),8.60(d, J=2 Hz, 1H)

Example 11641-(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-1-(pyridin-3-yl)ethanol

303 mg of the title compound was obtained as yellow crystals by treating350 mg of(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]-benzothiazin-8-yl)(pyridin-3-yl)ketonewith methyllithium by the same method as the one of Production Example86.

¹H-NMR(CDCl₃) δ ppm: 1.95(s, 3H), 2.38(br.s, 1H), 3.43(s, 3H), 5.18(d,J=10 Hz, 1H), 5.21(d, J=10 Hz, 1H), 6.97(d, J=8 Hz, 1H), 6.99(dd, J=2, 8Hz, 1H), 7.21(d, J=2 Hz, 1H), 7.25(dd, J=5, 8 Hz, 1H), 7.63(td, J=2, 8Hz, 1H), 7.83(d, J=3 Hz, 1H), 7.84(d, J=3 Hz, 1H), 8.50(dd, J=2, 5 Hz,1H), 8.70(d, J=2 Hz, 1H)

Example 11658-[1-(Pyridin-3-yl)vinyl]-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine

To a solution of 303 mg of1-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)1-(pyridin-3-yl)ethanolin dichloromethane was added in a nitrogen atmosphere 0.32 ml of methylchlorosulfonate and the resulting mixture was heated under reflux for 2hours. Then the reaction mixture was brought back to room temperatureand distributed into water and ethyl acetate. The extract was dried overanhydrous magnesium sulfate and filtered. After distilling off thesolvent under reduced pressure, the residue was purified by silica gelcolumn chromatography (eluted with dichloromethane/methanol) to therebygive 230 mg of the title compound as a yellow solid.

¹H-NMR(CDCl₃) δ ppm: 3.39(s, 3H), 5.21(s, 2H), 5.50(s, 1H), 5.59(s, 1H),6.91(dd, J=2, 8 Hz, 1H), 7.00(d, J=8 Hz, 1H), 7.07(d, J=2 Hz, 1H),7.29(br.s, 1H), 7.62(br.d, J=8 Hz, 1H), 7.85(d, J=3 Hz, 1H), 7.86(d, J=3Hz, 1H), 8.59(br.m, 1H), 8.65(br.m, 1H)

Example 11668-[1-(Pyridin-3-yl)ethyl]-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine

0.23 g of8-[1-(pyridin-3-yl)vinyl]-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazinewas dissolved in 10 ml of ethanol and then hydrogenated in the presenceof 0.056 g of 10% palladium-carbon (moisture content: 50%) in a hydrogengas stream at room temperature for 26 hours. Thus 0.106 g of the titlecompound was obtained as yellow crystals.

¹H-NMR(CDCl₃) δ ppm: 1.63(d, J=7 Hz, 3H), 3.45(s, 3H), 4.11(q, J=7 Hz,1H), 5.20(s, 2H), 6.82(dd, J=2, 8 Hz, 1H), 6.96(d, J=8 Hz, 1H), 6.98(d,J=2 Hz, 1H), 7.23(dd, J=5, 8 Hz, 1H), 7.50(td, J=2, 8 Hz, 1H), 7.85(m,2H), 8.46(br.m, 1H), 8.53(br.m, 1H)

Examples

The following compounds were obtained by the same method as the one ofExample 9.

Ex. Structural formula MS M.p. NMR 1167

FAB(+) 329 (MH⁺) 183-184° C. ¹H-NMR(CDCl₃) δ ppm: 6.54(br.s, 1H),6.61(d, J=1Hz, 1H), 6.91(dd, J=1, 8Hz, 1H), 6.95(d, J=8Hz, 1H), 7.38(dd,J=5, 8Hz, 1H), 7.59(d, J=3Hz, 1H), 7.73(d, J=3Hz, 1H), 7.80(d, J=8Hz,1H), 8.71(d, J=5Hz, 1H), 8.75(s, 1H) 1168

FAB(+) 311 (MH⁺) 157-159° C. ¹H-NMR(DMSO-d₆) δ ppm: 6.63(d, J=46Hz, 1H),6.77(s, 1H), 6.78(d, J=8Hz, 1H), 6.95(d, J=8Hz, 1H), 7.46(dd, J=5, 8Hz,1H), 7.63(s, 2H), 7.74(d, J=8Hz, 1H), 8.60(br.s, 2H), 9.53(s, 1H) 1169

FAB(+) 323 (MH⁺) 156-188° C. ¹H-NMR(CDCl₃) δ ppm: 3.37(s, 3H),5.11(br.s, 1H), 6.40(br.s, 1H), 6.50(d, J=1Hz, 1H), 6.78(dd, J=1, 8Hz,1H), 6.85(d, J=8Hz, 1H), 7.27(dd, J=5, 8Hz, 1H), 7.57(d, J=3Hz, 1H),7.61(td, J=2, 8Hz, 1H), 7.70(d, J=3Hz, 1H), 8.53(dd, J=2, 5Hz, 1H),8.57(d, J=2Hz, 1H) 1170

FAB(+) 307 (MH⁺) 180-181° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.50(d, J=7Hz, 3H),4.03(q, J=7Hz, 1H), 6.66(d, J=1Hz, 1H), 6.71(dd, J=1, 8Hz, 1H), 6.84(d,J=8Hz, 1H), 7.31(dd, J=5, 8Hz, 1H), 7.59(td, J=2, 8Hz, 1H), 7.62(s, 2H),8.39(dd, J=2, 5Hz, 1H), 8.46(d, J=2Hz, 1H), 9.39(s, 1H)

Example 1171(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-[2-[(trimethylsilyl)ethynyl]pyridin-5-yl]methanol

0.198 g of the title compound was obtained by treating 0.215 g of(10-methoxymethyl-10H-pyrazino[2,3-][1,4]benzothiazin-8-yl)-(2-bromopyridin-5-yl)methanolby the same method as the one of Example 1417.

¹H-NMR(CDCl₃) δ ppm: 0.27(s, 9H), 2.41(s, 1H), 3.40(s, 3H), 5.24(s, 2H),5.82(s, 1H), 6.92(dd, J=2, 8 Hz, 1H), 7.00(d, J=8 Hz, 1H), 7.15(d, J=2Hz, 1H), 7.40(d, J=8 Hz, 1H), 7.65(dd, J=2, 8 Hz, 1H), 7.85(d, J=3 Hz,1H), 7.86(d, J=3 Hz, 1H), 8.51(d, J=2 Hz, 1H)

Example 1172(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-(2-ethynylpyridin-5-yl)methanol

0.316 g of the title compound was obtained by treating 0.392 g of(10-methoxymethyl-10H-pyrazin[2,3-b][1,4]benzothiazin-8-yl)-[2-[(trimethylsilyl)ethynyl]pyridin-5-yl]methanolwith tetra-n-butylammonium fluoride by the same method as the one ofExample 1418.

¹H-NMR(CDCl₃) δ ppm: 2.36(d, J=4 Hz, 1H), 3.15(s, 1H), 3.49(s, 3H),5.23(s, 2H), 5.82(d, J=4 Hz, 1H), 6.93(dd, J=2, 8 Hz, 1H), 7.00(d, J=8Hz, 1H), 7.14(d, J=2 Hz, 1H), 7.45(d, J=8 Hz, 1H), 7.66(dd, J=2, 8 Hz,1H), 7.84(d, J=3 Hz, 1H), 7.85(d, J=3 Hz, 1H), 8.62(d, J=2 Hz, 1H)

Example 1173(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-(2-ethylpyridin-5-yl)methanol

0.262 g of the title compound was obtained by treating 0.316 g of(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-(2-ethynylpyridin-5-yl)methanolby the same method as the one of Example 20.

¹H-NMR(CDCl₃) δ ppm: 1.28(t, J=7 Hz, 3H), 2.39(s, 1H), 2.81(q, J=7 Hz,2H), 3.47(s, 3H), 5.22(d, J=9 Hz, 1H), 5.26(d, J=9 Hz, 1H), 5.80(s, 1H),6.96(dd, J=2, 8 Hz, 1H), 7.00(d, J=8 Hz, 1H), 7.14(d, J=8 Hz, 1H),7.17(d, J=2 Hz, 1H), 7.58(dd, J=2, 8 Hz, 1H), 7.84(d, J=3 Hz, 1H),7.85(d, J=3 Hz, 1H), 8.55(d, J=2 Hz, 1H)

Example 1174Methyl[5-[(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]-benzothiazin-8-yl)hydroxymethyl]pyridin-2-ylthiol]acetate

To a solution of 0.106 g of methyl thioacetate in N,N-dimethylformamide(8 ml) was added in a nitrogen atmosphere 0.040 g of sodium hydride (60%oily) and the resulting mixture was stirred for 15 minutes. After adding0.215 g of(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-(2-bromopyridin-5-yl)methanol,the resulting mixture was stirred at room temperature for 14 hours andheated to 60° C. for 2 hours. Then the reaction mixture was distributedinto water and ethyl acetate and the aqueous layer was extracted withethyl acetate. The organic layer was washed with water and dried overanhydrous sodium sulfate. After distilling off the solvent under reducedpressure, the residue was purified by silica gel column chromatography(eluted with n-hexane/ethyl acetate) to thereby give 0.128 g of thetitle compound as a yellow solid.

¹H-NMR(CDCl₃) δ ppm: 3.48(s, 3H), 3.74(s, 3H), 3.97(s, 2H), 5.23(s, 2H),5.74(s, 1H), 6.92(dd, J=2, 8 Hz, 1H), 7.00(d, J=8 Hz, 1H), 7.05(d, J=2Hz, 1H), 7.44(d, J=8 Hz, 1H), 7.54(d, J=8 Hz, 1H), 7.83(m, 2H),8.40(br.s, 1H)

Examples

The following compounds were obtained by treating the compounds obtainedin Examples 1173 and 1174 by the same method as the one of Example 9.

Ex. Structural formula MS M.p. NMR 1175

FAB(+) 337 (MH⁺) 161-163° C. ¹H-NMR(CDCl₃) δ ppm: 1.30(t, J=7Hz, 3H),2.82(q, J=7Hz, 2H), 5.70(s, 1H), 6.55(s, 1H), 6.60(s, 1H), 6.81(d,J=8Hz, 1H), 6.86(d, J=8Hz, 1H), 7.17(d, J=9Hz, 1H), 7.55(d, J=3Hz, 1H),7.58(dd, J=1, 9Hz, 1H), 7.68(d, J=3Hz, 1H), 8.51(d, J=1Hz, 1H) 1176

FAB(+) 399 (MH⁺) 65-70° C. solvent unknown 3.91(s, 2H), 5.53(d, J=4Hz,1H), 6.02(d, J=4Hz, 1H), 6.75(dd, J=1, 8Hz, 1H), 6.81(d, J=1Hz, 1H),6.84(d, J=8Hz, 1H), 7.26(d, J=8Hz, 1H), 7.50(dd, J=2, 8Hz, 1H), 7.62(d,J=3Hz, 1H), 7.63(d, J=3Hz, 1H), 8.35(d, J=2Hz, 1H), 9.44(s, 1H)

Example 1177(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-(6-bromopyridin-2-yl)methanol

30 ml of a solution of 2.84 g of 2,6-dibromopyridine in diethyl etherwas cooled in a nitrogen atmosphere in a methanol/liquefied nitrogenbath to −85° C. and 7.5 ml of a 1.6 M solution of n-butyllithium inhexane was dropped thereinto. After stirring for 30 minutes, thereaction mixture was heated to −78° C. and 40 ml of a solution of 1.05 gof(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbaldehydein dry tetrahydrofuran was dropped thereinto. Then the reaction mixturewas brought back to room temperature and distributed into an aqueoussolution of sodium dihydrogenphosphate and ethyl acetate. The aqueouslayer was extracted with ethyl acetate, washed successively with waterand a saturated aqueous solution of sodium chloride and dried overanhydrous sodium sulfate followed by filtration. After distilling offthe solvent under reduced pressure, the residue was purified by silicagel column chromatography (eluted with dichloromethane/methanol) tothereby give 1.05 g of the title compound as a yellow solid.

¹H-NMR(CDCl₃) δ ppm: 3.51(s, 3H), 4.40(d, J=5 Hz, 1H), 5.25(s, 2H),5.66(d, J=5 Hz, 1H), 6.98(m, 2H), 7.16(d, J=8 Hz, 1H), 7.17(s, 1H),7.40(d, J=8 Hz, 1H), 7.50(t, J=8 Hz, 1H), 7.83(d, J=3 Hz, 1H), 7.84(d,J=3 Hz, 1H)

Example 11788-[(6-Bromopyridin-2-yl)-(tert-butyldimethylsiloxy)methyl]-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine

To a solution of 1.05 g of(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-(6-bromopyridin-2-yl)methanolin 15 ml of acetonitrile was added in a nitrogen atmosphere 3.2 ml ofN-(tert-butyldimethylsilyl)-N-methyltrifluoroacetamide and the resultingmixture was stirred at room temperature for 22 hours. After distillingoff the solvent under reduced pressure, the residue was purified bysilica gel column chromatography (eluted with n-hexane/ethyl acetate) tothereby give 0.72 g of the title compound as a yellow solid.

¹H-NMR(CDCl₃) δ ppm: 0.01(s, 3H), 0.04(s, 3H), 0.93(s, 9H), 3.53(s, 3H),5.23(s, 2H), 5.77(s, 1H), 6.93(d, J=8 Hz, 1H), 7.09(dd, J=2, 8 Hz, 1H),7.31(dd, J=2, 7 Hz, 1H), 7.36(d, J=2 Hz, 1H), 7.48(dd, J=2, 7 Hz, 1H),7.51(t, J=7 Hz, 1H), 7.82(m, 2H)

Example 1179Ethyl(E)-3-[6-[(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]-benzothiazin-8-yl)-(tert-butyldimethylsiloxy)methyl]pyridin-2-yl]-2-propenoate

To a solution of 0.72 g of8-[(6-bromopyridin-2-yl)-(tert-butyldimethylsiloxy)methyl]-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazinein N,N-dimethylformamide (8 ml) were added 0.17 ml of ethyl acrylate,0.22 ml of triethylamine, 12 mg of palladium (II) acetate and 33 mg oftriphenylphosphine and the resulting mixture was heated to 90° C. for 30hours. Then the reaction mixture was brought back to room temperatureand distributed into water and ethyl acetate. The organic layer wasextracted, washed successively with water and a saturated aqueoussolution of sodium chloride, dried over anhydrous magnesium sulfate andfiltered. After distilling off the solvent under reduced pressure, theresidue was purified by silica gel column chromatography (diluted withdichloromethane/ethyl acetate) to thereby give 540 mg of the titlecompound as a yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 0.01(s, 3H), 0.07(s, 3H), 0.96(s, 9H), 1.35(t, J=7Hz, 3H), 3.53(s, 3H), 4.28(q, J=7 Hz, 2H), 5.23(s, 2H), 5.82(s, 1H),6.84(d, J=8 Hz, 1H), 6.94(d, J=16 Hz, 1H), 7.12(dd, J=2, 8 Hz, 1H),7.25(d, J=8 Hz, 1H), 7.42(d, J=2 Hz, 1H), 7.50(d, J=8 Hz, 1H), 7.65(d,J=16 Hz, 1H), 7.67(t, J=8 Hz, 1H), 7.82(s, 2H)

Example 1180Ethyl3-[6-[(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]-benzothiazin-8-yl)-(tert-butyldimethylsiloxy)methyl]pyridin-2-yl]propanoate

201 mg of the title compound was obtained by treating 249 mg of ethyl3-[6-[(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]-benzothiazin-8-yl)-(tert-butyldimethylsiloxy)methyl]pyridin-2-yl]-2-propenoateby the same method as the one of Example 20.

¹H-NMR(CDCl₃) δ ppm: 0.05(s, 3H), 0.03(s, 3H), 0.93(s, 9H), 1.20(t, J=7Hz, 3H), 2.77(m, 2H), 3.06(m, 2H), 3.51(s, 3H), 4.11(q, J=7 Hz, 2H),5.22(s, 2H), 5.74(s, 1H), 6.91(d, J=8 Hz, 1H), 7.00(d, J=8 Hz, 1H),7.06(dd, J=2, 8 Hz, 1H), 7.30(d, J=8 Hz, 1H), 7.36(d, J=2 Hz, 1H),7.53(t, J=8 Hz, 1H), 7.81(s, 2H)

Examples

The following compounds were obtained by treating the compounds obtainedin Examples 1179 and 1180 with tetrabutylammonium fluoride by the samemethod as the one of Example 1418 and followed by the same treatment asthe one of Example 9.

Ex. Structural formula MS M.p. NMR 1181

ESI (+) 429 (MNa⁺) 160-170° C. (decom- pose) ¹H-NMR(CDCl₃) δ ppm:1.37(t, J=7Hz, 3H), 4.30(q, J=7Hz, 2H), 5.59(s, 1H), 6.86(s, 2H),6.99(d, J=16Hz, 1H), 7.12(d, J=8Hz, 1H), 7.12(d, J=8Hz, 1H), 7.35(d,J=8Hz, 1H), 7.55(d, J=3Hz, 1H), 7.67(d, J=3Hz, 1H), 7.69(t, J=8Hz, 1H),7.69(d, J=16Hz, 1H) 1182

ESI (+) 431 (MNa⁺) ¹H-NMR(CDCl₃) δ ppm: 1.24(t, J=7Hz, 3H), 2.83(t,J=6Hz, 2H), 3.18(t, J=6Hz, 2H), 4.14(q, J=7Hz, 2H), 5.52(s, 1H), 6.51(s,1H), 6.66(s, 1H), 6.84(s, 2H), 6.94(d, J=8Hz, 1H), 7.12(d, J=8Hz, 1H),7.53(d, J=3Hz, 1H), 7.55(t, J=8Hz, 1H), 7.60(d, J=3Hz, 1H)

Example 1183(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)(pyridin-2-yl)ketone

The title compound was synthesized by oxidizing(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-(pyridin-3-yl)methanolwith manganese dioxide by the same method as the one of Example 625.

¹H-NMR(CDCl₃) δ ppm: 3.47(s, 3H), 5.30(s, 2H), 7.10(d, J=8.2 Hz, 1H),7.50(ddd, J=1.3, 4.3, 7.6 Hz, 1H), 7.70(dd, J=1.5, 8.2 Hz, 1H), 7.85(s,2H), 7.87(d, J=1.5 Hz, 1H), 7.91(dt, J=1.9, 7.6 Hz, 1H), 8.05(d, J=1.3,7.6 Hz, 1H), 8.72(d, J=1.9, 4.3 Hz, 1H)

Example 11841-(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-2-(pyridin-2-yl)ethanol

90 mg of the title compound was obtained as a yellow oily substance bytreating 260 mg of 2-methylpyridine and(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbaldehydeby the same method as the one of Example 1128.

¹H-NMR(CDCl₃) δ ppm: 3.10(d, J=5.9 Hz, 2H), 3.52(s, 3H), 5.10(d, J=5.9Hz, 1H), 5.25(s, 2H), 5.8-6.0(br.s, 1H), 6.97(d, J=7.9 Hz, 1H), 7.02(dd,J=1.6, 7.9 Hz, 1H), 7.11(br.d, J=7.5 Hz, 1H), 7.19(br.dd, J=5.0, 7.5 Hz,1H), 7.21(br.d, J=1.6 Hz, 1H), 7.62(dt, J=1.8, 7.5 Hz, 1H), 7.82(s, 2H),8.52(br.d, J=5.0 Hz, 1H)

Example 1185(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-yl)(pyridin-2-yl)ketone

The title compound was obtained by treating(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)(pyridin-2-yl)ketoneby the same method as the one of Example 9.

¹H-NMR(DMSO-d₆) δ ppm: 7.05(d, J=8.6 Hz, 1H), 7.35(d, J=1.6 Hz, 1H),7.37(dd, J=1.6, 8.6 Hz, 1H), 7.65(d, J=3.2 Hz, 1H), 7.66(dd, J=4.3, 7.6Hz, 1H), 7.67(d, J=3.2 Hz, 1H), 7.92(d, J=7.6 Hz, 1H), 8.04(dt, J=1.6,7.6 Hz, 1H), 8.70(dd, J=1.6, 4.3 Hz, 1H), 9.64(s, 1H)

Example 11861-(10H-Pyrazino-[2,3-b][1,4]benzothiazin-8-yl)-2-(pyridin-2-yl)ethanol

The following compound was obtained by treating1-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-2-(pyridin-2-yl)ethanolby the same method as the one of Example 434.

¹H-NMR(DMSO-d₆) δ ppm: 2.89(dd, J=5.5, 13.5 Hz, 1H), 2.95(dd, J=8.3,13.5 Hz, 1H), 4.79(ddd, J=4.3, 5.5, 13.5 Hz, 1H), 5.37(d, J=4.3 Hz, 1H),6.69(dd, J=1.3, 8.3 Hz, 1H), 6.80(d, J=8.3 Hz, 1H), 6.81(d, J=1.3 Hz,1H), 7.17(d, J=7.6 Hz, 1H), 7.18(t, J=4.3 Hz, 1H), 7.62(d, J=3.2 Hz,1H), 7.63(d, J=3.2 Hz, 1H), 7.64(dt, J=1.7, 7.6 Hz, 1H), 8.47(d, J=4.3Hz, 1H), 9.46(s, 1H)

MS: FAB(+)325(MH⁺)

Example 1187(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-yl)(pyridin-2-ylmethyl)ketone

0.15 ml of diisopropylamine in tetrahydrofuran (10 ml) was ice-cooledand 1.0 ml of a 1.6 M solution of n-butyllithium in hexane was addedthereto. After stirring for 10 minutes, the reaction mixture was cooledto −78° C. After adding 0.15 ml of 2-methylpyridine, the mixture wasstirred for 30 minutes and then a solution of 303 mg ofmethyl(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carboxylatein tetrahydrofuran (5 ml) was dropped thereinto. The reaction mixturewas brought back to room temperature and distributed into an aqueoussolution of ammonium chloride and ethyl acetate. The organic layer wasextracted, dried over anhydrous sodium sulfate and filtered. Afterdistilling off the solvent under reduced pressure, the residue waspurified by silica gel column chromatography (eluted with n-hexane/ethylacetate) to thereby give 30 mg of(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)(pyridin-2-ylmethyl)ketoneas yellow crystals. This ketone was further treated by the same methodas the one of Example 119 to thereby give 13 mg of the title compound asyellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 4.36(s, initial, 2H, keto), 6.68(s, initial 1H,enol), 6.94 and 7.04(d, J=8.8 Hz, total 1H, enol:keto=8:1), 7.12 and7.25(t, J=6.4 Hz, total 1H, 8:1), 7.25 and 7.33(d, J=8.8 Hz, total 1H,8:1), 7.25 and 7.44(d, J=8.0 Hz, total 1H, 8:1), 7.26 and 7.28(s, total1H, 8:1), 7.53(d, J=2.4 Hz, total 1H), 7.54(d, J=2.4 Hz, total 1H), 8.37and 8.44(t, J=6.4 Hz, total 1H, 8:1), 8.73 and 8.78(t, J=8.0 Hz, total1H, 1:8), 9.57 and 9.64(s, total 1H, 8:1)

MS: FAB(+)321(M⁺)

Example 1188 (10H-Pyrazino[2,3-b][1,4]benzothiazin-8-yl)hydroxyaceticacid

5 ml of an aqueous solution of 780 mg of potassium hydroxide and 300 mgof lithium chloride was ice-cooled. Into the mixture was dropped 5 ml ofa solution of 900 mg of bromoform and 960 mg of(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbaldehydein dioxane. After stirring at 0° C. to room temperature over day andnight, the reaction mixture was distributed into dilute hydrochloricacid and ethyl acetate. The organic layer was extracted with ethylacetate, washed with water and dried over anhydrous sodium sulfate andthen the extract was filtered. After distilling off the solvent underreduced pressure, the residue was purified by silica gel columnchromatography (eluted with dichloromethane/methanol). Afterrecrystallizing from ethyl acetate, 260 mg of the title compound wasobtained as yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 4.81(s, 1H), 6.81(dd, J=1.5, 8.2 Hz, 1H), 6.84(d,J=1.5 Hz, 1H), 6.86(d, J=8.2 Hz, 1H), 7.62(d, J=2.8 Hz, 1H), 7.63(d,J=2.8 Hz, 1H)

MS: FAB(+)275(M⁺), 276(MH⁺)

Example 1189Methyl(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)hydroxyacetate

150 mg of methyl iodide was added to a solution of 100 mg of(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)hydroxyacetic acid inN,N-dimethylformamide (8 ml) in the presence of 260 mg of potassiumcarbonate. After purifying by silica gel column chromatography (elutedwith dichloromethane/methanol) and recrystallizing from ethylacetate/diisopropyl ether, 68 mg of the title compound was obtained asyellow crystals.

¹H-NMR(CDCl₃) δ ppm: 3.48-3.68(br.s, 1H), 3.77(s, 3H), 5.01(s, 1H),6.58(s, 1H), 6.65-6.71(br.s, 1H), 6.88(s, 2H), 7.57(d, J=2.7 Hz, 1H),7.69(d, J=2.7 Hz, 1H)

Example 1190Methyl3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-3-hydroxypropanoate

820 mg of(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]-benzothiazin-8-yl)carbaldehydewas dissolved in tetrahydrofuran (5 ml)/trimethyl borate (5 ml) in anitrogen atmosphere and 195 mg of zinc dust (400-mesh) was addedthereto. After stirring, 460 mg of methyl bromoacetate was further addedto the reaction mixture. After heating under reflux for 8 hours, thereaction mixture was brought back to room temperature and distributedinto an aqueous solution of ammonium chloride and ethyl acetate. Theorganic layer was extracted, washed with water and dried over anhydroussodium sulfate and the extract was filtered. After distilling off thesolvent under reduced pressure, the residue was purified by silica gelcolumn chromatography (eluted with dichloromethane/methanol) to therebygive 300 mg of methyl3-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-3-hydroxypropanoateas a yellow oily substance. A 100 mg portion of this product was treatedby the same method as the one of Example 9 to thereby give 30 mg of thetitle compound as yellow crystals.

¹H-NMR(CDCl₃) δ ppm: 2.68(d, J=9.2 Hz, 2H), 3.35(br.d, J=3.3 Hz, 1H),3.73(s, 3H), 4.99(dt, J=3.3, 9.2 Hz, 1H), 6.50(br.s, 1H), 6.59(dd,J=1.3, 8.2 Hz, 1H), 6.87(d, J=8.2 Hz, 1H), 6.95(d, J=1.3 Hz, 1H)7.58(d,J=2.6 Hz, 1H), 7.70(d, J=2.6 Hz, 1H)

Example 11913-(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-3-hydroxypropanoicacid

80 mg of the title compound was obtained as yellow crystals by treating100 mg of methyl3-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-3-hydroxypropanoateby the same method as the one of Example 18.

¹H-NMR(CDCl₃) δ ppm: 2.68(dd, J=3, 14 Hz, 1H), 2.74(dd, J=9, 14 Hz, 1H),3.49(s, 3H), 5.03(dd, J=3, 9 Hz, 1H), 5.24(s, 2H), 6.90(d, J=8.5 Hz,1H), 6.92(d, J=8.5 Hz, 1H), 7.10(s, 1H), 7.80(s, 2H)

Example 11923-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-yl)-3-hydroxypropanoic acid

40 mg of the title compound was obtained as yellow crystals by treating3-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-3-hydroxypropanoicacid by the same method as the one of Example 434.

¹H-NMR(DMSO-d₆) δ ppm: 2.43(d, J=6.9 Hz, 2H), 4.72(t, J=6.9 Hz, 1H),5.39-5.46(br.s, 1H), 6.73(d, J=7.8 Hz, 1H), 6.79(d, J=1.4 Hz, 1H),6.83(dd, J=1.4, 7.8 Hz, 1H), 7.61(d, J=3.2 Hz, 1H), 7.62(d, J=3.2 Hz,1H), 9.48(s, 1H), 12.06-12.17(br.s, 1H)

MS: FAB(+)289(M⁺)

Example 11931-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-yl)-1,3-propanediol

50 mg of the title compound was obtained as yellow crystals by treating100 mg of methyl3-(10-methoxymethyl-10H-pyrazion[2,3-b][1,4]benzothiazin-8-yl)-3-hydroxypropanoateby the same methods as those of Examples 2 and 434.

¹H-NMR(DMSO-d₆) δ ppm: 1.52-1.71(m, 2H), 3.30-3.41(m, 1H), 3.41-3.52(m,1H), 4.41(t, J=5.2 Hz, 1H), 4.40-4.48(m, 1H), 5.12(d, J=4.3 Hz, 1H),6.71(d, J=7.6 Hz, 1H), 6.77(s, 1H), 6.82(d, J=7.6 Hz, 1H), 7.61(d, J=2.4Hz, 1H), 7.63(d, J=2.4 Hz, 1H), 9.47(s, 1H)

MS: FAB(+)275(M⁺)

Example 11948-Vinyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine

To 2.94 g of methyltriphenylphosphonium bromide in N,N-dimethylformamide(20 ml) was added at room temperature 360 mg of sodium hydride (60%oily) and the resulting mixture was stirred for 1 hour. Next, 1.50 g of(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbaldehydewas added thereto and the resulting mixture was heated to 65° C. for 1.5hours. Then the reaction mixture was brought back to room temperatureand distributed into water and ethyl acetate. The organic layer wasextracted, washed with water and dried over anhydrous sodium sulfate andthe extract was filtered. After distilling off the solvent under reducedpressure, the residue was purified by silica gel column chromatography(eluted with n-hexane/ethyl acetate) to thereby give 1.42 g of the titlecompound as a yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 3.53(s, 3H), 5.26(d, J=10.9 Hz, 1H), 5.30(s, 2H),5.72(d, J=17.5 Hz, 1H), 6.63(dd, J=10.9, 17.5 Hz, 1H), 6.96(d, J=7.9 Hz,1H), 7.03(dd, J=1.7, 7.9 Hz, 1H), 7.18(d, J=1.7 Hz, 1H), 7.83(s, 2H)

Example 11951-(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-1,2-ethanediol

To 30 ml of a solution of 2.6 g of8-vinyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine and 1.06g of N-methylmorpholine oxide in acetone was added 4.2 ml of a 1%solution of osmium tetraoxide in tert-butanol and the resulting mixturewas stirred at room temperature for 12 hours. Then it was distributedinto an aqueous solution of sodium hydrogenthiosulfate and ethylacetate. After filtering off the inorganic matters through celite, theorganic layer was extracted, washed with water and dried over anhydroussodium sulfate and the extract was filtered. After distilling off thesolvent under reduced pressure, the residue was purified by silica gelcolumn chromatography (eluted with dichloromethane/methanol) to therebygive 0.35 g of the title compound as yellow crystals.

¹H-NMR(CDCl₃) δ ppm: 3.50(s, 3H), 3.59(dd, J=8.1, 11.4 Hz, 1H), 3.71(dd,J=3.0, 11.4 Hz, 1H), 4.71(dd, J=3.0, 8.1 Hz, 1H), 5.24(s, 2H), 6.90(dd,J=1.4, 7.9 Hz, 1H), 6.94(d, J=7.9 Hz, 1H), 7.10(d, J=1.4 Hz, 1H),7.81(s, 2H)

Example 11961-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-yl)-1,2-ethanediol

100 mg of the title compound was obtained as yellow crystals by treating350 mg of1-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-1,2-ethanediolby the same method as the one of Example 9.

¹H-NMR(DMSO-d₆) δ ppm: 3.24-3.43(m, 2H), 4.32(t, J=5.5 Hz, 1H), 6.73(d,J=8.4 Hz, 1H), 6.78(d, J=1.4 Hz, 1H), 6.82(dd, J=1.4, 8.4 Hz, 1H),7.61(d, J=3.4 Hz, 1H), 7.62(d, J=3.4 Hz, 1H), 9.46(s, 1H)

MS: FAB(+)261(M⁺), 262(MH⁺)

Examples

The following compounds were obtained by treating(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbaldehyde successively bythe same methods as those of Examples 1128 and 9.

Ex. Structural formula MS M.p. NMR 1197

192-194° C. ¹H-NMR(CDCl₃) δ ppm: 5.54(br.s, 1H), 6.50(br.s, 1H), 6.77(s,1H), 6.92(d, J=8Hz, 1H), 7.05(d, J=8Hz, 1H), 7.28-7.40(m, 4H),7.43-7.48(m, 2H), 7.58(d, J=3Hz, 1H), 7.67(d, J=3Hz, 1H) 1198

ESI312 (MH⁺) 116-118° C. ¹H-NMR(CDCl₃) δ ppm: 1.20(t, J=6Hz, 3H), 1.34-1.48(m, 2H), 1.50-1.60(m, 2H), 2.15-2.20(br.s, 1H), 2.25(dt, J=2, 6Hz,2H), 5.28-5.35(br.s, 1H), 6.43- 6.50(br.s, 1H), 6.72(s, 1H), 6.88(d,J=8Hz, 1H), 6.97(d, J=8Hz, 1H), 7.57(d, J=3Hz, 1H), 7.69(d, J=3Hz, 1H)

Example 11991-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-yl)-3-phenylpropan-1-ol

The title compound was obtained by treating1-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-3-phenyl-2-propyn-1-ol bythe same method as the one of Example 20.

¹H-NMR(CDCl₃) δ ppm: 1.90-2.10(m, 2H), 2.60-2.80(m, 2H), 4.50-4.60(br.s,1H), 6.40-6.46(br.s, 1H), 6.52(s, 1H), 6.78(d, J=8 Hz, 1H), 6.85(d, J=8Hz, 1H), 7.15-7.23(m, 2H), 7.25-7.30(m, 4H), 7.58(d, J=3 Hz, 1H),7.72(d, J=3 Hz, 1H)

MS: ESI(+)336(MH⁺)

m.p.: 156-158° C.

Example 1200(E)-3-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-yl)-2-propen-1-ol

The title compound was obtained as yellow crystals by treating(E)-3-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-2-propen-1-olby the same method as the one of Example 434.

¹H-NMR(D, O-d₆) δ ppm: 4.07(dd, J=4.9, 5.5 Hz, 2H), 4.87(t, J=5.5 Hz,1H), 6.21(dt, J=4.9, 16.2 Hz, 1H), 6.33(d, J=16.2 Hz, 1H), 6.79(s, 1H),6.84(s, 2H), 7.61-7.65(m, 2H), 9.47(s, 1H)

Example 12013-(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-1-propanol

6.0 g of the title compound was obtained as yellow crystals by treating7.5 g of ethyl3-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)propanoateby the same method as the one of Example 2 followed by purification bysilica gel column chromatography (eluted with dichloromethane/methanol).

¹H-NMR(CDCl₃) δ ppm: 1.33-1.38(m, 1H), 1.87(dt, J=7.0, 14.9 Hz, 2H),2.66(dd, J=7.0, 9.3 Hz, 2H), 3.53(s, 3H), 3.65-3.72(m, 2H), 5.28(s, 2H),6.83(dd, J=1.6, 7.7 Hz, 1H), 6.94(d, J=7.7 Hz, 1H), 7.00(d, J=1.6 Hz,1H), 7.82(d, J=2.8 Hz, 1H), 7.84(d, J=2.8 Hz, 1H)

Example 1202 3-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-yl)-1-propanol

120 mg of the title compound was obtained as yellow crystals by treating250 mg of3-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-1-propanolby the same method as the one of Example 434.

¹H-NMR(CDCl₃) δ ppm: 1.33-1.45(br.s, 1H), 1.83(quint, J=7.1 Hz, 2H),2.58(t, J=7.1 Hz, 2H), 3.68(t, J=7.1 Hz, 2H), 6.36(d, J=1.9 Hz, 1H),6.46-6.53(br.s, 1H), 6.69(dd, J=1.9, 7.9 Hz, 1H), 6.81(d, J=7.9 Hz, 1H),7.57(d, J=2.8 Hz, 1H), 7.69(d, J=2.8 Hz, 1H)

Example 1203(E)-5-(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-2-hydroxy-2-methyl-4-penten-3-one

550 mg of(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbaldehydeand 3-hydroxy-3-methyl-2-butanone was dissolved in methanol (10ml)/tetrahydrofuran (2 ml). After adding 250 mg of lithium hydroxide,the reaction mixture was stirred at room temperature over day and night.Then the reaction mixture was distributed into an aqueous solution ofammonium chloride and ethyl acetate. The organic layer was extracted,washed with water and dried over anhydrous sodium sulfate. Afterfiltering, the filtrate was distilled off under reduced pressure and theresidue was purified by silica gel column chromatography (eluted withdichloromethane/methanol) to thereby give 420 mg of the title compoundas a yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.45(s, 6H), 3.55(s, 3H), 3.92(s, 1H), 5.29(s, 2H),6.96(d, J=15.7 Hz, 1H), 7.03(d, J=8.0 Hz, 1H), 7.23(dd, J=1.7, 8.0 Hz,1H), 7.30(d, J=1.7 Hz, 1H), 7.75(d, J=15.7 Hz, 1H), 7.85(d, J=2.8 Hz,1H), 7.86(d, J=2.8 Hz, 1H)

Example 1204(E)-5-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-yl)-2-hydroxy-2-methyl-4-penten-3-one

320 mg of the title compound was obtained as yellow crystals by treating420 mg of(E)-5-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-2-hydroxy-2-methyl-1-penten-3-oneby the same method as the one of Example 9.

¹H-NMR(DMSO-d₆) δ ppm: 1.23(s, 6H), 5.43(s, 1H), 6.97(d, J=8.2 Hz, 1H),7.06(s, 1H), 7.12(d, J=8.2 Hz, 1H), 7.33(d, J=16.9 Hz, 1H), 7.37(d,J=16.9 Hz, 1H), 7.64(d, J=3.0 Hz, 1H), 7.65(d, J=3.0 Hz, 1H), 9.51(s,1H)

Example 12055-(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-2-hydroxy-2-methylpentan-3-one

320 mg of the title compound was obtained as yellow crystals by treating450 mg of(E)-5-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-2-hydroxy-2-methyl-4-penten-3-onesuccessively by the same methods as those of Examples 20 and 9.

¹H-NMR(DMSO-d₆) δ ppm: 1.14(s, 6H), 2.55(t, J=7 Hz, 2H), 2.88(t, J=7 Hz,2H), 5.24(br.s, 1H), 6.61(t, J=1 Hz, 1H), 6.63(dd, J=1, 8 Hz, 1H),6.79(dd, J=1, 8 Hz, 1H), 7.62(m, 2H), 9.43(s, 1H)

MS: FAB(+)315(M⁺)

Example 1206 1-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-yl)ethanol

5.0 g of(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbaldehydewas treated by the same method as the one of Production Example 86 tothereby give 5.0 g of1-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)ethanol asa yellow oily substance. Next, a 0.5 g portion of this product wastreated by the same method as the one of Example 9 to thereby give 0.1 gof the title compound as yellow crystals.

¹H-NMR(CDCl₃) δ ppm: 1.43(d, J=4.0 Hz, 3H), 1.91(br.s, 1H), 4.78(q,J=4.0 Hz, 1H), 6.50-6.60(br.s, 1H), 6.57(d, J=1.6 Hz, 1H), 6.81(dd,J=1.6, 8.3 Hz, 1H), 6.86(d, J=8.3 Hz, 1H), 7.57(d, J=3.1 Hz, 1H),7.69(d, J=3.1 Hz, 1H)

Example 1207Diethyl(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)phosphonate

To 2 ml of triethyl phosphite was added 0.374 g of8-chloromethyl-10H-pyrazino[2,3-b][1,4]benzothiazine and the resultingmixture was heated to 160° C. for 3 hours. Then the reaction mixture wasbrought back to room temperature and diethyl ether (10 ml) and n-hexane(20 ml) were added thereto. The precipitate was taken up by filtrationand washed several times with n-hexane to thereby give 0.413 g of thetitle compound as a yellow powder.

¹H-NMR(CDCl₃) δ ppm: 1.28(t, J=6 Hz, 6H), 2.94(d, J=23 Hz, 2H), 4.05(m,4H), 6.50(s, 1H), 6.51(d, J=2 Hz, 1H), 6.73(dd, J=2, 8 Hz, 1H), 6.82(d,J=8 Hz, 1H), 7.57(d, J=3 Hz, 1H), 7.69(d, J=3 Hz, 1H)

MS: FAB(+)352(MH⁺)

m.p.: 164-165° C.

Example 12085-(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-1,3-oxazole

To 10 ml of a solution of 560 mg of(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbaldehydein methanol were added 280 mg of potassium carbonate and 392 mg of(p-toluenesulfonyl)methyl isocyanide and the resulting mixture washeated under reflux for 1.5 hours. Then the reaction mixture was broughtback to room temperature and diluted with water. The crystals thusprecipitated were taken up by filtration and washed successively withwater and diethyl ether to thereby give 400 mg of the title compound asyellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 3.41(s, 3H), 5.33(s, 2H), 7.22(d, J=8.2 Hz, 1H),7.37(dd, J=1.7, 8.2 Hz, 1H), 7.39(d, J=1.7 Hz, 1H), 7.68(s, 1H), 7.94(d,J=2.8 Hz, 1H), 7.98(d, J=2.8 Hz, 1H), 8.45(s, 1H)

Example 12091-(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-1,3-butanedione

Into 20 ml of ice-cooled solution of 1.27 ml of diisopropylamine in drytetrahydrofuran was dropped in a nitrogen atmosphere 5.5 ml of a 1.6 Msolution of n-butyllithium in hexane. After stirring for 10 minutes, thereaction mixture was cooled to −78° C. Next, 5 ml of a solution of 2.0 gof (10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)methylketone in dry tetrahydrofuran was added thereto and the mixture wasstirred for 30 minutes. After further dropping 700 mg of acetyl chloridethereinto, the reaction mixture was brought back to room temperature.Then the reaction mixture was distributed into water and ethyl acetateand the organic layer was extracted, washed with water, dried overanhydrous sodium sulfate and filtered. The filtrate was distilled offunder reduced pressure and the residue was purified by silica gel columnchromatography (eluted with toluene/acetone) to thereby give 420 mg ofthe title compound as a yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 2.20(s, 3H), 3.56(s, 3H), 5.33(s, 2H), 6.10(s, 1H),7.06(d, J=7.8 Hz, 1H), 7.43(dd, J=1.6, 7.8 Hz, 1H), 7.64(d, J=1.6 Hz,1H), 7.86(s, 2H)

Example 12108-(5-Methylpyrazol-3-yl)10H-pyrazino[2,3-b][1,4benzothiazine

To 10 ml of a solution of 180 mg of1-(10-methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-1,3-butanedionein methanol was added 50 mg of hydrazine monohydrate and the resultingmixture was heated under reflux for 30 minutes. Then the reactionmixture was brought back to room temperature. After distilling off thesolvent under reduced pressure, the crystals thus precipitated weretaken up by filtration and washed with diethyl ether to thereby give 150mg of8-(5-methylpyrazol-3-yl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazineas yellow crystals. Further, this product was treated by the same methodas the one of Example 9 to thereby give 110 mg of the title compound asyellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 2.22(br.s, 3H), 6.27(s, 1H), 6.89(br.d, J=8.0 Hz,1H), 7.12(d, J=8.0 Hz, 1H), 7.23(br.s, 1H), 7.63(d, J=2.9 Hz, 1H),7.64(d, J=2.9 Hz, 1H), 9.52(br.s, 1H), 12.50-12.60(br.s, 1H)

MS: FAB(+)285(M⁺)

Example 1211(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-yl)-3-methylisoxazole

Similar to Example 1223,1-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-1,3-butanedionewas treated with hydroxylamine to thereby give(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-3-methylisoxazole.Further, this product was treated by the same method as the one ofExample 9 to thereby give the title compound.

¹H-NMR(DMSO-d₆) δ ppm: 2.26(s, 3H), 6.72(s, 1H), 7.04(d, J=8.0 Hz, 1H),7.15(d, J=1.4 Hz, 1H), 7.21(dd, J=1.4, 8.0 Hz, 1H), 7.66(d, J=3.0 Hz,1H), 7.67(d, J=3.0 Hz, 1H), 9.65(s, 1H)

Example 12122-Amino-1-[N-[(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)methylene]]aminobenzene

820 mg of(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbaldehydeand 360 mg of o-phenylenediamine were suspended in 2 ml of pyridine in anitrogen atmosphere and heated under reflux for 10 minutes. Then thereaction mixture was brought back to room temperature and a small amountof ethyl acetate was added thereto. The crystals thus precipitated wereground by ultrasonication and filtered. Thus 610 mg of the titlecompound was obtained as yellow crystals.

¹H-NMR(CDCl₃) δ ppm: 3.57(s, 3H), 4.26(br.s, 2H), 5.35(s, 2H), 6.75(dt,J=1.2, 7.4 Hz, 1H), 6.78(dd, J=1.2, 7.4 Hz, 1H), 7.07(d, J=7.4 Hz, 1H),7.08(t, J=7.4 Hz, 1H), 7.09(d, J=8.3 Hz, 1H), 7.50(dd, J=1.5, 8.3 Hz,1H), 7.66(d, J=1.5 Hz, 1H), 7.86(s, 2H), 8.46(s, 1H)

Example 12138-(Benzimidazol-2-yl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine

610 mg of2-amino-1-[N-[(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)methylene]]aminobenzenewas heated under reflux in 3 ml of pyridine for 8 hours. Then thereaction mixture was brought back to room temperature and eluted withethyl acetate. The crystals thus precipitated were ground and filteredto thereby give 310 mg of the title compound as yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 3.45(s, 3H), 5.39(s, 2H), 7.15-7.25(m, 2H),7.31(d, J=8.3 Hz, 1H), 7.48-7.56(br.d, J=7.2 Hz, 1H), 7.63-7.70(br.d,J=7.2 Hz, 1H), 7.75(dd, J=1.7, 8.3 Hz, 1H), 7.94(d, J=1.7 Hz, 1H),7.96(d, J=2.6 Hz, 1H), 8.00(d, J=2.6 Hz, 1H), 12.93(br.s, 1H)

Example 12148-(Benzothiazol-2-yl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine

Similar to Example 1212, 2-aminobenzenethiol employed as a substitutefor o-phenylenediamine was heated under reflux in pyridine for 30minutes to thereby give 820 mg of(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbaldehyde,from which 250 mg of the title compound was obtained as yellow crystals.

¹H-NMR(CDCl₃) δ ppm: 3.61(s, 3H), 5.40(s, 2H), 7.13(t, J=8.1 Hz, 1H),7.40(t, J=8.3 Hz, 1H), 7.50(t, J=8.3 Hz, 1H), 7.68(dd, J=1.8, 8.1 Hz,1H), 7.85(d, J=1.8 Hz, 1H), 7.88(s, 2H), 7.90(d, J=8.3 Hz, 1H), 8.07(d,J=8.3 Hz, 1H)

Examples

The following compounds were obtained each as yellow crystals bytreating the compounds obtained in Examples 1213 and 1214 by the samemethod as the one of Example 434.

Ex. Structural formula NMR 1215

¹H-NMR(DMSO-d₆) δ ppm: 7.09(d, J=7.7Hz, 1H), 7.13- 7.23(m, 2H),7.45-7.52(m, 1H), 7.48(dd, J=1.7, 7.7Hz, 1H), 7.59-7.65(m, 1H), 7.63(d,J=1.7Hz, 1H), 7.66(d, J=2.7Hz, 1H), 7.68(d, J=2.7Hz, 1H), 9.70(s, 1H),12.83(br.s, 1H) 1216

¹H-NMR(DMSO-d₆) δ ppm: 7.08(d, J=8.1Hz, 1H), 7.44(dd, J=1.8, 8.1Hz, 1H),7.45(t, J=8.0Hz, 1H), 7.52(d, J=1.8Hz, 1H), 7.53(t, J=8.0Hz, 1H),7.67(d, J=2.8Hz, 1H), 7.68(d, J=2.8Hz, 1H), 8.01(d, J=8.0Hz, 1H),8.13(d, J=8.0Hz, 1H), 9.69(s, 1H)

Example 1217(E)-8-(Benzenesulfonylvinyl)-10-methoxymethyl-10H-pyrazino-[2,3-b][1,4]benzothiazine

A solution of 1.40 g of diethyl(benzenesulfonyl)-methylphosphonate inN,N-dimethylformamide (15 ml) was cooled to 0° C. in a nitrogenatmosphere. After adding 210 mg of sodium hydride, the resulting mixturewas stirred for 5 minutes. Into the reaction mixture was dropped asolution of 1.00 g of(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbaldehydein N,N-dimethylformamide (5 ml). After stirring for additional 10minutes, the reaction mixture was distributed into water and ethylacetate. The organic layer was extracted, washed with water and driedover magnesium sulfate. After distilling off the solvent under reducedpressure, the residue was diluted with diisopropyl ether and thecrystals thus precipitated were filtered to thereby give 1.38 g of thetitle compound as yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 3.36(s, 3H), 5.33(s, 2H), 7.18(d, J=8.0 Hz, 1H),7.35(d, J=1.7 Hz, 1H), 7.40(dd, J=1.7, 8.0 Hz, 1H), 7.58(s, 2H),7.62-7.69(m, 2H), 7.70-7.75(m, 1H), 7.89-7.93(m, 2H), 7.95(d, J=2.9 Hz,1H), 7.97(d, J=2.9 Hz, 1H)

Example 12188-(1,2,3-Triazol-4(5)-yl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine

To a solution of 410 mg of8-(2-benzenesulfonylvinyl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazinein a mixture of N,N-dimethylformamide (3 ml) and dimethyl sulfoxide (7ml) was added sodium azide (450 mg in total) and the resulting mixturewas heated to 120° C. for 3 hours. Then the reaction mixture was broughtback to room temperature and distributed into 1 N hydrochloric acid andethyl acetate. The organic layer was extracted, washed with water anddried over anhydrous magnesium sulfate. After distilling off the solventunder reduced pressure, the crystals thus precipitated were filtered andwashed with diisopropyl ether. Thus 220 mg of the title compound wasobtained.

¹H-NMR(DMSO-d₆) δ ppm:

3.41(s, 3H), 5.33(s, 2H), 7.19 and 7.21(d, J=7.7 Hz, total 1H, 1:2),7.47 and 7.49(dd, J=1.4, 7.7 Hz, total 1H, 1:2), 7.62 and 7.69(d, J=1.4Hz, total 1H, 2:1), 7.94(d, J=2.8 Hz, 1H), 7.98(d, J=2.8 Hz, 1H), 8.23and 8.57(d, J=1.2 Hz, initial 1H, and, br.s, initial 1H, 2:1)

Example 12198-(3-Trimethylsilylpyrazol-4-yl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine

1.5 ml of a 2.0 M solution of (trimethylsilyl)-diazomethane in hexanewas added to dry tetrahydrofuran (7 ml) in a nitrogen atmosphere andcooled to −78° C. After dropping 1.0 ml of a 1.6 M n-butyllithiumsolution in n-hexane thereinto, the resulting mixture was stirred for 30minutes. Into the reaction mixture was dropped a solution of 410 mg of8-(2-benzenesulfonylvinyl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazineobtained in Example 1080-1 in dry tetrahydrofuran (5 ml). Then thereaction mixture was gradually heated to room temperature and an aqueoussolution of ammonium chloride was added thereto followed by extractionwith ethyl acetate. Then the mixture was dried over anhydrous sodiumsulfate. After distilling off the solvent under reduced pressure, theobtained residue was purified by silica gel column chromatography(eluted with ethyl acetate/n-hexane) to thereby give 130 mg of the titlecompound as yellow crystals.

¹H-NMR(CDCl₃) δ ppm: 0.00(s, 9H), 3.20(s, 3H), 4.96(s, 2H), 6.68(dd,J=1.5, 7.6 Hz, 1H), 6.72(d, J=7.6 Hz, 1H), 6.68(d, J=1.5 Hz, 1H),7.38(s, 1H), 7.54(d, J=2.8 Hz, 1H), 7.55(d, J=2.8 Hz, 1H)

Example 12208-(Pyrazol-4-yl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine

5 ml of a solution of 130 mg of8-(3-trimethylsilyl-pyrazol-4-yl)-10-methoxymethyl-10H-pyrazino(2,3-b][1,4]-benzothiazinein tetrahydrofuran was stirred at room temperature and 1.1 ml of a 1Msolution of tetrabutylammonium fluoride in tetrahydrofuran was addedthereto. After stirring for 5 minutes, the reaction mixture wasdistributed into ethyl acetate and 1 N hydrochloric acid. The organiclayer was extracted, washed with water and dried over anhydrous sodiumsulfate. After distilling off the solvent under reduced pressure, theobtained residue was purified by silica gel column chromatography(eluted with dichloromethane/methanol) to thereby give 42 mg of thetitle compound as yellow crystals.

¹H-NMR(CDCl₃) δ ppm: 3.56(s, 3H), 5.33(s, 2H), 7.03(d, J=7.8 Hz, 1H),7.12(dd, J=1.6, 7.8 Hz, 1H), 7.32(d, J=1.6 Hz, 1H), 7.85(s, 2H), 7.85(d,J=2.8 Hz, 1H), 7.86(d, J=2.8 Hz, 1H)

Example 12218-(1,2,3-Triazol-4(5)-yl)-10H-pyrazino[2,3-b][1,4-benzothiazine

The title compound was obtained by treating8-(1,2,3-triazol-4(5)-yl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]-benzothiazineby the same method as the one of Example 434.

¹H-NMR(DMSO-d₆ ) δ ppm: 6.69(d, J=8.6 Hz, 1H), 7.23(d, J=8.6 Hz, 1H),7.27-7.35(br.s, 1H), 7.64(d, J=3.0 Hz, 1H), 7.65(d, J=3.0 Hz, 1H),8.12-8.27(br.s, 1H), 9.61(s, 1H)

MS: FAB(+)269(MH⁺)

Example 1222 8-(Pyrazol-4-yl)10H-pyrazino[2,3-b][1,4]benzothiazine

The title compound was obtained by treating8-(pyrazol-4-yl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazineby the same method as the one of Example 9.

¹H-NMR(DMSO-d₆) δ ppm: 6.88(d, J=7.6 Hz, 1H), 6.96(d, J=1.8 Hz, 1H),7.02(dd, J=1.8, 7.6 Hz, 1H), 7.63(d, J=2.9 Hz, 1H), 7.64(d, J=2.9 Hz,1H), 7.87(br.s, 2H), 9.44(s, 1H)

MS: FAB(+)268(MH⁺)

Example 1223(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbaldehydeoxime

To 10 ml of a solution of 820 mg of(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbaldehydeand 430 mg of ammonium acetate in ethanol was added 1 ml of an aqueoussolution of 230 mg of hydroxylamine hydrochloride. Then the resultingmixture was heated under reflux for 1 hour while adding tetrahydrofuranif necessary. The reaction mixture was brought back to room temperatureand the solvent was distilled off under reduced pressure. The crystalsthus precipitated were taken up by filtration and washed successivelywith water and diethyl ether to thereby give 760 mg of the titlecompound as yellow crystals.

¹H-NMR(CDCl₃) δ ppm: 3.54(s, 3H), 5.30(s, 2H), 7.02(d, J=8.0 Hz, 1H),7.14(dd, J=1.6, 8.0 Hz, 1H), 8.38(d, J=1.6 Hz, 1H), 7.58(s, 1H), 7.85(d,J=3.1 Hz, 1H), 7.86(d, J=3.1 Hz, 1H), 8.06(s, 1H)

Example 1224(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbonitrile

100 mg of(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbaldehydeoxime was suspended in 2 ml of trichloroacetonitrile in a nitrogenatmosphere and heated under reflux for 30 minutes. After distilling offthe low-boiling fraction, the crystals thus precipitated were groundafter adding diethyl ether thereto and taken up by filtration to therebygive 90 mg of the title compound as colorless crystals.

¹H-NMR(CDCl₃) δ ppm: 3.54(s, 3H), 5.26(s, 2H), 7.08(d, J=7.8 Hz, 1H),7.22(dd, J=1.6, 7.8 Hz, 1H), 7.38(d, J=1.6 Hz, 1H), 7.88(d, J=2.7 Hz,1H), 7.90(d, J=2.7 Hz, 1H)

Example 12258-(Tetrazol-5-yl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine

To a solution of 150 mg of(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbonitrilein dimethyl sulfoxide were added 360 mg of sodium azide and 300 mg ofammonium chloride and the resulting mixture was heated to 100° C. for 4hours. Then the reaction mixture was brought back to room temperatureand distributed into ethyl acetate and 1 N hydrochloric acid. Theorganic layer was extracted, washed with water and dried over anhydroussodium sulfate. After distilling off the solvent under reduced pressure,the obtained residue was purified by silica gel column chromatography(eluted with dichloromethane/methanol/acetic acid) to thereby give 130mg of the title compound as yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 3.43(s, 3H), 5.32(s, 2H), 7.35(d, J=7.9 Hz, 1H),7.61(dd, J=1.7, 7.9 Hz, 1H), 7.76(d, J=1.7 Hz, 1H), 7.96(d, J=2.6 Hz,1H), 8.00(d, J=2.6 Hz, 1H)

Example 1226 8-(Tetrazol-5-yl)10H-pyrazino[2,3-b][1,4]benzothiazine

40 mg of8-(tetrazol-5-yl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazinewas heated 5 ml of glacial acetic acid to 60° C. for 30 minutes. Afterthe completion of the reaction, silica gel was added thereto. Afterdistilling off the solvent under reduced pressure, the residue waspurified by silica gel column chromatography (eluted withdichloromethane/methanol/acetic acid) to thereby give 18 mg of the titlecompound as yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 7.13(d, J=8.2 Hz, 1H), 7.34(dd, J=1.7, 8.2 Hz,1H), 7.45(d, J=1.7 Hz, 1H), 7.67(d, J=3.0 Hz, 1H), 7.68(d, J=3.0 Hz,1H), 9.77(s, 1H)

MS: FAB(+)270(MH⁺)

Example 1227[N-(2-Pyridyl)aminometyl](10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)ketone

To 3 ml of a solution of 140 mg of 2-aminopyridine in ethanol was added130 mg of sodium hydrogencarbonate and the resulting mixture was stirredat room temperature. Next, 2 ml of a solution of 360 mg ofbromomethyl(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)ketonein tetrahydrofuran was dropped thereinto and the resulting mixture washeated under reflux for 2 hours. Then the reaction mixture was broughtback to room temperature and silica gel was added thereto. Afterdistilling off the solvent under reduced pressure, the residue waspurified by silica gel column chromatography (eluted withdichloromethane/methanol) to thereby give 200 mg of the title compoundas yellow crystals.

¹H-NMR(CDCl₃) δ ppm: 3.47(s, 2H), 3.58(s, 3H), 5.41(s, 2H), 6.78(dt,J=0.9, 6.7 Hz, 1H), 7.06(d, J=8.3 Hz, 1H), 7.18(ddd, J=1.3, 6.7, 9.1 Hz,1H), 7.55(dd, J=1.7, 8.3 Hz, 1H), 7.62(br.d, J=9.1 Hz, 1H), 7.72(d,J=1.7 Hz, 1H), 7.83(s, 1H), 7.84(s, 2H), 8.11(br.d, J=6.7 Hz, 1H)

Example 12288-(Imidazo[1,2-a]pyridin-3-yl)-10H-pyrazino[2,3-b][1,41-benzothiazine

10 ml of a solution of 200 mg of[N-(2-pyridyl)aminometyl](10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)ketonein carbon tetrachloride was stirred at room temperature and 240 mg ofthionyl chloride was dropped thereinto. The reaction mixture wasdistributed into dichloromethane and an aqueous solution of sodiumbicarbonate and the organic layer was separated. To the organic layerwere added methanol and tetrahydrofuran to give a homogeneous solution.After adding silica gel and distilling off the solvent under reducedpressure, the residue was purified by silica gel column chromatography(eluted with dichloromethane/methanol) to thereby give 103 mg of thetitle compound as yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 6.88(dt, J=1.1, 7.7 Hz, 1H), 6.95(d, J=7.7 Hz,1H), 7.23(ddd, J=1.1, 7.0, 9.5 Hz, 1H), 7.37(dd, J=1.8, 7.7 Hz, 1H),7.44(d, J=1.8 Hz, 1H), 7.53(d, J=9.5 Hz, 1H), 7.63(d, J=2.6 Hz, 1H),7.65(d, J=2.6 Hz, 1H), 8.26(s, 1H), 8.52(dd, J=1.1, 7.0 Hz, 1H), 9.59(s,1H)

MS: FAB(+)218(MH⁺)

Example 12298-(1,3-Thiazol-5-yl)-10-methoxymethyl-10H-pyrazino2,3-b][1,4]benzothiazine

To 3 ml of a solution of 180 mg of crude thioformamide in ethanol wasadded 130 mg of sodium hydrogencarbonate and the resulting mixture wasstirred at room temperature. After dropping 2 ml of a solution of 360 mgofbromomethyl(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)ketonein tetrahydrofuran, the resulting mixture was stirred for 1 hour. Thenthe reaction mixture was distributed into water and ethyl acetate. Theorganic layer was extracted and dried over anhydrous sodium sulfate.After distilling off the solvent under reduced pressure, the residue waspurified by silica gel column chromatography (eluted with ethylacetate/n-hexane) to thereby give 100 mg of the title compound as yellowcrystals.

¹H-NMR(DMSO-d₆) δ ppm: 3.42(s, 3H), 5.33(s, 2H), 7.20(d, J=8.3 Hz, 1H),7.61(dd, J=1.5, 8.3 Hz, 1H), 7.78(d, J=1.5 Hz, 1H), 7.94(d, J=2.4 Hz,1H), 7.98(d, J=2.4 Hz, 1H), 8.17(d, J=2.0 Hz, 1H), 9.19(d, J=2.0 Hz, 1H)

Example 12308-(Imidazo[2,1-b]benzothiazol-1-yl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine

180 mg of the title compound was obtained as yellow crystals by the samemethod as the one of Example 1229 by starting with 550 mg ofbromomethyl(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]-benzothiazin-8-yl)ketoneand 300 mg of 2-aminobenzothiazole.

¹H-NMR(DMSO-d₆) δ ppm: 3.46(s, 3H), 5.35(s, 2H), 7.18(d, J=8.3 Hz, 1H),7.42(t, J=7.6 Hz, 1H), 7.48(dd, J=1.6, 8.3 Hz, 1H), 7.56(t, J=7.6 Hz,1H), 7.68(d, J=1.6 Hz, 1H), 7.94(d, J=2.6 Hz, 1H), 7.98(d, J=2.6 Hz,1H), 8.00(d, J=7.6 Hz, 1H), 8.03(d, J=7.6 Hz, 1H), 8.77(s, 1H)

Examples

The following compounds were obtained each as yellow crystals bytreating the compounds obtained in Examples 1229 and 1230.

Ex. Structural formula MS NMR 1231

FAB(+) 284(M⁺) ¹H-NMR(DMSO-d₆) δ ppm: 6.98(d, J=8.4Hz, 1H), 7.16(dd,J=1.5, 8.4Hz, 1H), 7.45(d, J=1.5Hz, 1H), 7.62-7.65(m, 2H), 8.02(d,J=1.8Hz, 1H), 9.16(d, J=1.8Hz, 1H), 9.59(s, 1H) 1232

¹H-NMR(DMSO-d₆) δ ppm: 6.95(d, J=8.1Hz, 1H), 7.23(dd, J=1.6, 8.1Hz, 1H),7.33(d, J=1.6Hz, 1H), 7.42(t, J=7.7Hz, 1H), 7.55(t, J=7.7Hz, 1H),7.64(d, J=3.1Hz, 1H), 7.66(d, J=3.1Hz, 1H), 8.00(d, J=7.7Hz, 1H),8.02(d, J=7.7Hz, 1H), 8.65(s, 1H), 9.63(s, 1H)

Example 12332-(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-4,5-dihydro-1,3-thiazol-4-ol

450 mg of(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbothioamidewas dissolved in a solvent mixture of tetrahydrofuran (5 ml) with1,2-dimethoxyethane (5 ml). Under stirring, 610 mg of potassiumhydrogencarbonate and 2 ml of a 40% chloroacetaldehyde solution wereadded thereto at room temperature and the resulting mixture was stirredfor half a day. Then the reaction mixture was distributed into anaqueous solution of ammonium chloride and ethyl acetate. The organiclayer was extracted and dried over anhydrous sodium sulfate. Afterdistilling off the solvent, the crystals thus precipitated were taken upby filtration to thereby give 475 mg of the title compound as yellowcrystals.

¹H-NMR(CDCl₃) δ ppm: 3.41(dd, J=4.5, 11.8 Hz, 1H), 3.56(s, 3H), 3.63(dd,J=6.9, 11.8 Hz, 1H), 5.33(s, 2H), 6.28(dd, J=4.5, 6.9 Hz, 1H), 7.05(d,J=8.2 Hz, 1H), 7.43(dd, J=1.5, 8.2 Hz, 1H), 7.64(d, J=1.5 Hz, 1H),7.86(s, 2H)

Example 1234 8-(Thiazol-2-yl)-10H-pyrazino[2,3-b][1,4]benzothiazine

450 mg of2-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-4,5-dihydro-1,3-thiazol-4-oland 0.83 ml of pyridine were dissolved in 15 ml of 1,2-dimethoxyethane.While stirring the reaction mixture under ice-cooling, 300 mg oftrifluoroacetic anhydride was dropped thereinto and the resultingmixture was stirred for 1 hour. Then the reaction mixture wasdistributed into an aqueous solution of sodium bicarbonate and ethylacetate. The organic layer was extracted, washed with water and driedover anhydrous magnesium sulfate. After distilling off the solvent underreduced pressure, the oily residue thus obtained was treated in the samemanner as the one of Example 434 and purified by silica gel columnchromatography (eluted with dichloromethane/methanol). Thus 230 mg ofthe title compound was obtained as yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 7.01(d, J=7.7 Hz, 1H), 7.31(dd, J=1.9, 7.7 Hz,1H), 7.39(d, J=1.9 Hz, 1H), 7.66(d, J=2.4 Hz, 1H), 7.67(d, J=2.4 Hz,1H), 7.76(d, J=3.2 Hz, 1H), 7.89(d, J=3.2 Hz, 1H), 9.66(s, 1H)

Example 12358-(3H,4H-Dihydrothiazol-2-ylmethyl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine

670 mg of 2-aminoethanethiol hydrochloride was suspended in 20 ml ofmethanol. Then 1.2 g of a 28% solution of sodium methoxide in methanolwas added thereto and the resulting mixture was subjected toultrasonication at room temperature for about 5 minutes. Next, 570 mg of(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbaldehydewas added thereto and the resulting mixture was heated under reflux for3 hours. The reaction mixture was then distributed into water and ethylacetate. The organic layer was extracted, washed with water and driedover anhydrous sodium sulfate. After distilling off the solvent underreduced pressure, the residue was purified by silica gel columnchromatography (eluted with dichloromethane/methanol) to thereby give510 mg of the title compound as a yellow oily substance.

¹H-NMR(DMSO-d₆) δ ppm: 3.29(t, J=8.5 Hz, 2H), 3.53(s, 3H), 3.76(s, 2H),4.25(t, J=8.5 Hz, 2H), 5.27(s, 2H), 6.90(dd, J=1.4, 8.0 Hz, 1H), 6.97(d,J=8.0 Hz, 1H), 7.08(d, J=1.4 Hz, 1H), 7.83(d, J=2.7 Hz, 1H), 7.84(d,J=2.7 Hz, 1H)

Example 12368-(3H,4H-Dihydrothiazol-2-ylmethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine

15 mg of the title compound was obtained as yellow crystals by treating400 mg of8-(3H,4H-dihydrothiazol-2-ylmethyl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazineby the same method as the one of Example 434.

¹H-NMR(DMSO-d₆) δ ppm: 3.25(t, J=8.6 Hz, 2H), 3.60(s, 2H), 4.12(t, J=8.6Hz, 2H), 6.65(s, 1H), 6.67(d, J=7.8 Hz, 1H), 6.84(d, J=7.8 Hz, 1H),7.63(s, 2H), 9.48(s, 1H).

Example 1237N-(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)phthalimide

A solution of 3.32 g of(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)methanol,2.12 g of phthalimide and 3.77 g of triphenylphosphine intetrahydrofuran (50 ml) was ice-cooled and 2.24 ml of diethylazodicarboxylate was dropped thereinto. After stirring at roomtemperature for 1 hour, the solvent was distilled off under reducedpressure and diethyl ether was added to the residue. Then it wassubjected to ultrasonication and the crystals thus precipitated weretaken up by filtration to thereby give 2.6 g of the title compound aspale yellow crystals.

¹H-NMR(CDCl₃) δ ppm: 3.51(s, 3H), 4.76(s, 2H), 5.22(s, 2H), 6.95(d,J=7.9 Hz, 1H), 7.03(dd, J=1.7, 7.9 Hz, 1H), 7.21(d, J=1.7 Hz, 1H),7.71(dd, J=3.0, 5.4 Hz, 2H), 7.82(s, 2H), 7.84(dd, J=3.0, 5.4 Hz, 2H)

Example 1238N-(-10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)phthalimide

7.9 g of the title compound was obtained as yellow crystals by treating10.0 g ofN-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)phthalimideby the same method as the one of Example 434.

¹H-NMR(DMSO-d₆) δ ppm: 4.58(s, 2H), 6.68(s, 1H), 6.74(d, J=7.6 Hz, 1H),6.86(d, J=7.6 Hz, 1H), 7.61(s, 2H), 7.85(dd, J=2.9, 5.7 Hz, 2H),7.90(dd, J=2.9, 5.7 Hz, 2H), 9.42(s, 1H)

Example 1239 8-(Aminomethyl)10H-pyrazino[2,3-b][1,4]benzothiazine

7.9 g of N-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)phthalimidewas suspended in hydrazine monohydrate (10 ml)/ethanol (50 ml) and thereaction mixture was heated to 80° C. for 20 minutes. Then the reactionmixture was brought back to room temperature. After distilling off thesolvent under reduced pressure, the residue was distributed into anaqueous solution of potassium carbonate and ethyl acetate. The organiclayer was extracted and dried over anhydrous sodium sulfate. Afterdistilling off the solvent under reduced pressure, the residue thusobtained was purified by silica gel column chromatography (eluted withdichloromethane/methanol/aqueous ammonia) to thereby give 5.0 g of thetitle compound as yellow orthorhombic crystals.

¹H-NMR(CDCl₃) δ ppm: 3.72(s, 2H), 6.50(d, J=1.4 Hz, 1H), 6.74(dd, J=1.4,7.9 Hz, 1H), 6.81(d, J=7.9 Hz, 1H), 7.09-7.20(br.s, 1H), 7.54(d, J=2.7Hz, 1H), 7.66(d, J=2.7 Hz, 1H)

Example 1240N-[3-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-yl)propyl]phthalimide

The title compound was obtained as yellow crystals by treating3-(10H-pyrazino[2,3-b][1,4]-benzothiazin-8-yl)propanol with phthalimideby the same method as the one of Example 1237 followed by the sametreatment as the one of Example 434.

¹H-NMR(DMSO-d₆) δ ppm: 1.83(quint, J=7.2 Hz, 2H), 2.43(t, J=7.2 Hz, 2H),3.58(t, J=7.2 Hz, 2H), 6.56(s, 1H), 6.61(d, J=7.8 Hz, 1H), 6.72(d, J=7.8Hz, 1H), 7.51(d, J=3.3 Hz, 1H), 7.53(d, J=3.3 Hz, 1H), 7.72-7.77(m, 2H),7.77-7.82(m, 2H), 9.38(s, 1H)

Example 1241 8-(Aminomethyl)10H-pyrazino[2,3-b][1,4]benzothiazinehydrochloride

To a solution of 5.0 g of8-(aminomethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine in a mixture ofdry methanol (5 ml)/ethyl acetate (30 ml) was added 10 ml of a solutionof 22 g of hydrogen chloride in 500 ml of ethyl acetate and theresulting mixture was subjected to ultrasonication. To the crystals thusprecipitated was added diethyl ether followed by filtration. Thus, thetitle compound was obtained as orange crystals almost quantitatively.

¹H-NMR(DMSO-d₆) δ ppm: 3.79(br.q, J=5.7 Hz, 2H), 6.73(d, J=1.7 Hz, 1H),6.90(dd, J=1.7, 7.8 Hz, 1H), 6.95(d, J=7.8 Hz, 1H), 7.64(d, J=3.1 Hz,1H), 7.66(d, J=3.1 Hz, 1H), 8.25-8.45(br.s, 3H), 9.70(s, 1H)

Example 1242 8-(3-Aminopropyl)-10H-pyrazino[2,3-b][1,4]benzothiazinehydrochloride

The title compound was obtained by treatingN-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-propyl]phthalimidesuccessively by the same methods as those of Examples 1239 and 1241.

¹H-NMR(CDCl₃) δ ppm: 1.73(quint, J=7.2 Hz, 2H), 2.45(t, J=7.2 Hz, 2H),2.68-2.80(m, 2H), 6.60(d, J=1.5 Hz, 1H), 6.64(dd, J=1.5, 8.0 Hz, 1H),6.83(d, J=8.0 Hz, 1H), 7.62(d, J=3.1 Hz, 1H), 7.63(d, J=3.1 Hz, 1H),7.82-8.02(br.s, 3H), 9.50(s, 1H)

Example 1243 α-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-yl)benzylamine

The title compound was obtained by treatingα-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)benzyl alcohol successivelyby the same methods as those of Examples 1237 and 1239.

¹H-NMR(CDCl₃) δ ppm: 5.03(s, 1H), 6.54(d, J=1.2 Hz, 1H), 6.78(d, J=7.8Hz, 1H), 6.82(dd, J=1.2, 7.8 Hz, 1H), 7.09-7.18(br.s, 1H), 7.20-7.26(m,2H), 7.28-7.33(m, 3H), 7.40(d, J=3.0 Hz, 1H), 7.41-7.47(br.s, 2H),7.60(d, J=3.0 Hz, 1H)

Example 12448-(N-Methyl)aminomethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine

8-Chloromethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazinewas stirred in a solution of methylamine in methanol at room temperatureover day and night. Then the reaction mixture was distilled underreduced pressure and the residue was distributed into sodium hydroxideand ethyl acetate. The organic layer was extracted and dried overanhydrous sodium sulfate. After distilling off the solvent under reducedpressure, the obtained residue was purified by silica gel columnchromatography (eluted with dichloromethane/methanol) to thereby givethe title compound as a yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 2.44(s, 3H), 3.53(s, 3H), 3.68(s, 2H), 5.29(s, 2H),6.93(dd, J=1.6, 7.8 Hz, 1H), 6.97(d, J=7.8 Hz, 1H), 7.10(d, J=1.6 Hz,1H), 7.82(d, J=2.8 Hz, 1H), 7.83(d, J=2.8 Hz, 1H)

Examples

The following compounds were obtained by treating8-chloromethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]-benzothiazineby the same method as the one of Example 1244.

Ex. Structural formula NMR 1245

¹H-NMR (CDCl₃) δ ppm: 2.20(s, 6H), 3.33(s, 2H), 3.47(s, 3H), 5.25(s,2H), 6.89(dd, J=1.5, 7.7Hz, 1H), 6.92(d, J=7.7Hz, 1H), 7.04(d, J=1.5Hz,1H), 7.77(d, J=2.9Hz, 1H), 7.78(d, J=2.9Hz, 1H) 1246

¹H-NMR (CDCl₃) δ ppm: 1.75(quint, J=8.1Hz, 2H), 2.21(s, 6H), 1.28(t,J=8.1Hz, 2H), 1.58(t, J=8.1Hz, 2H), 3.51(s, 3H), 5.26(s, 2H), 6.81(dd,J=1.5, 7.9Hz, 1H), 6.92(d, J=7.9Hz, 1H), 6.99(d, J=1.5Hz, 1H), 7.81(d,J=2.9Hz, 1H), 7.82(d, J=2.9Hz, 1H) 1247

¹H-NMR (CDCl₃) δ ppm: 2.22(s, 6H), 3.30(s, 2H), 3.52(s, 3H), 5.26(s,2H), 6.99(d, J=2.0Hz, 1H), 7.05(dd, J=2.0Hz, 8.5Hz, 1H), 7.08(d,J=8.5Hz, 1H), 7.81(d, J=2.7Hz, 1H), 7.82, J=2.7Hz, 1H)

Example 12488-(Dimethylamino)methyl-10H-pyrazino[2,3-b][1,4]benzothiazine

The title compound was obtained by treating8-(N-methyl)aminomethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazineby the same method as the one of Example 9.

¹H-NMR(CDCl₃) δ ppm: 2.40(s, 3H), 3.57(s, 2H), 6.50(d, J=1.6 Hz, 1H),6.73(dd, J=1.6, 7.9 Hz, 1H), 6.79(d, J=7.9 Hz, 1H), 7.10-7.38(br.s, 1H),7.53(d, J=2.6 Hz, 1H), 7.65(d, J=2.6 Hz, 1H)

Example 12498-(N-Methylaminomethyl)10H-pyrazino[2,3-b][1,4]benzothiazinehydrochloride

The title compound was obtained by treating8-(N-methylaminomethyl)10H-pyrazino[2,3-b][1,4]benzothiazine by the samemethod as the one of Example 1241.

¹H-NMR(DMSO-d₆) δ ppm: 2.48(s, 3H), 3.89(t, J=5.5 Hz, 2H), 6.75(d, J=1.4Hz, 1H), 6.93(dd, J=1.4, 7.8 Hz, 1H), 6.98(d, J=7.8 Hz, 1H), 7.64(d,J=3.2 Hz, 1H), 7.65(d, J=3.2 Hz, 1H), 8.93-9.10(m, 2H), 9.72(s, 1H)

Examples

The following compounds were obtained by treating successively by thesame methods as those of Examples 9 and 1241.

Ex. Structural formula NMR 1250

¹H-NMR (DMSO-d₆) δ ppm: 2.65(d, J=5.1Hz, 6H), 4.06(d, J=5,1Hz, 2H),6.76(s, 1H), 6.98(d, J=8.1Hz, 1H), 6.99(d, J=8.1Hz, 1H), 7.66(s, 2H),9.72(s, 1H), 10.38-10.50(m, 1H) 1251

¹H-NMR (DMSO-d₆) δ ppm: 1.86(quint, J=7.8Hz, 2H), 2.44(br.t, J=7.8Hz,2H), 2.68(d, J=5.0Hz, 6H), 2.93- 3.01(m, 2H), 6.62(s, 1H), 6.67(d,J=8.3Hz, 1H), 6.84(d, J=8.3Hz, 1H), 7.63(s, 2H), 9.50(s, 1H), 10.53-10.64(br.s, 1H) 1252

¹H-NMR (DMSO-d₆) δ ppm: 2.63(d, J=5.0Hz, 6H), 4.03(d, J=5.0Hz, 2H),6.78(d, J=7.9Hz, 1H), 7.10(d, J=1.7Hz, 1H), 7.12(dd, J=1.7, 7.9Hz, 1H),7.66(s, 2H), 9.69(s, 1H), 10.31- 10.44(m, 1H) 1253

¹H-NMR (DMSO-d₆) δ ppm: 3.90(t, J=5.5Hz, 2H), 4.10(t, J=5.5Hz, 2H),6.76(d, J=1.6Hz, 1H), 6.97(d, J=8.0Hz, 1H), 7.00(dd, J=1.6, 8.0Hz, 1H),7.38-7.45(m, 3H), 7.51(m, 2H), 7.65(d, J=2.9Hz, 1H), 7.66(d, J=2.9Hz,1H), 9.54- 9.68(m, 2H), 9.70(s, 1H)

Examples

The following compounds were obtained by treating8-chloromethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine bythe same method as the one of Example 1244.

Ex. Structural formula NMR 1254

¹H-NMR (CDCl₃) δ ppm: 3.44(s, 3H), 4.07(br.s, 1H), 4.29(d, J=5Hz, 2H),5.22(s, 2H), 6.62(d, J=8Hz, 2H), 6.72(t, J=8Hz, 1H), 6.98(s, 2H),7.13(s, 1H), 7.18(t, J=8Hz, 2H), 7.83(d, J=3Hz, 1H), 7.84(d, J=3Hz, 1H)1255

¹H-NMR (CDCl₃) δ ppm: 3.01(s, 3H), 3.35(s, 3H), 4.47(s, 2H), 5.14(s,2H), 6.68-6.78(m, 3H), 6.82- 6.86(m, 1H), 6.96(br.s, 1H), 6.95(d, J=7Hz,1H), 7.20-7.26(m, 2H), 7.82(d, J=3Hz, 1H), 7.83(d, J=3Hz, 1H)

Examples

The following compounds were obtained by treating the compounds given inthe above table by the same method as the one of Example 8.

Ex. Structural formula MS M. p. NMR 1256

ESI (+) 307 (MH⁺) 183-186° C. ¹H-NMR (CDCl₃) δ ppm: 4.0-4.2(m, 1H),4.21(s, 2H), 6.52(s, 1H), 6.59(d, J=8Hz, 1H), 6.68(br.s, 1H), 6.73(t,J=8Hz, 1H), 6.82(d, J=8Hz, 1H), 6.86(d, J=8Hz, 1H), 7.18(t, J=8Hz, 2H),7.50(d, J=3Hz, 1H), 7.66(d, J=3Hz, 1H) 1257

ESI (+) 321 (MH⁺) 172-174° C. ¹H-NMR (CDCl₃) δ ppm: 2.99(s, 3H), 4,37(s, 2H), 6.37(s, 1H), 6.66-6.78(m, 4H), 6.84(d, J=8Hz, 1H),7.20-7.28(m, 2H), 7.46(d, J=3Hz, 1H), 7.63(d, J=3Hz, 1H)

Example 12584-[N-[10-(Methoxymethyl)10H-pyrazino[2,3-b]-1,4]benzothiazin-8-ylmethyl]aminomethyl]benzenesulfonamide

The title compound was obtained by treating8-chloromethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazineand 4-aminomethylbenzenesuflonamide by the same method as the one ofExample 1244.

¹H-NMR(DMSO-d₆) δ ppm: 3.38(s, 3H), 3.59(s, 2H), 3.71(s, 2H), 5.25(s,2H), 6.96-7.02(m, 1H), 7.06(d, J=8 Hz, 1H), 7.14-7.16(m, 1H), 7.29(s,2H), 7.52(d, J=8 Hz, 2H), 7.75(d, J=8 Hz, 2H), 7.92(d, J=3 Hz, 1H),7.96(d, J=3 Hz, 1H)

Examples

The following compounds were obtained by treating8-chloromethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazinesuccessively by the same methods as those of Examples 1244 and 8.

Ex. Structural formula NMR 1259

¹H-NMR (DMSO-d₆) δ ppm: 1.30(t, J=7Hz, 3H), 3.48(s, 2H), 3.71(s, 2H),4.28(q, J=7Hz, 2H), 6.75(dd, J=2, 8Hz, 1H), 6.78(s, 1H), 6.83(d, J=8Hz,1H), 7.47(d, J=8Hz, 2H), 7.61(d, J=3Hz, 1H), 7.62(d, J=3Hz, 1H), 7.89(d,J=8Hz, 2H), 9.47(s, 1H) 1260

¹H-NMR (DMSO-d₆) δ ppm: 0.8-0.95(m, 2H), 1.14(t, J=7Hz, 3H),1.20-1.40(m, 3H), 1.70-1.90(m, 4H), 2.10-2.23(m, 1H), 2.20- 2.33(m, 2H),3.48(s, 2H), 4.0(q, J=7Hz, 2H), 6.70- 6.80(m, 1H), 6.75(s, 1H), 6.81(d,J=8Hz, 1H), 7.58- 7.68(m, 2H), 9.46(s, 1H)

Example 12614-[[N-[10-(Methoxymethyl)-10H-pyrazino[2,3-b][1,4]-benzothiazin-8-ylmethyl]-N-methyl]aminomethyl]benzene-sulfonamide

To a solution of 0.25 g of4-[[N-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]aminomethyl]-benzenesulfonamideand 0.45 ml of a 37% aqueous solution of formalin in acetonitrile (20ml) was added 57 mg of sodium borocyanohydride. After adjusting the pHvalue to 4 to 5 with acetic acid, the mixture was reacted at roomtemperature for 2 hours. After adding a 1 N aqueous solution of sodiumhydroxide, the reaction mixture was extracted with ethyl acetate, washedwith a saturated aqueous solution of sodium chloride and dried overanhydrous sodium sulfate. After distilling off the solvent under reducedpressure, the residue was purified by silica gel column chromatography(eluted with dichloromethane/methanol) to thereby give 110 mg of thetitle compound as a yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 2.20(s, 3H), 3.48(s, 3H), 3.56(s, 4H), 4.90(s, 2H),5.29(s, 2H), 6.96(s, 2H), 7.20(s, 1H), 7.52(d, J=8 Hz, 2H), 7.80-7.85(m,2H), 7.86(d, J=8 Hz, 2H)

Examples

The following compounds were obtained by the same method as the one ofExample 1261.

Ex. Structural formula NMR 1262

¹H-NMR (CDCl₃) δ ppm: 1.39(t, J=7Hz, 3H), 2.20(s, 3H), 3.47(s, 2H),3.55(s, 2H), 3.56(s, 3H), 4.37(q, J=7Hz, 2H), 5.29(s, 2H), 6.97(s, 2H),7.22(s, 1H), 7.45(d, J=8Hz, 2H), 7.84(s, 2H), 8.00(d, J=8Hz, 2H) 1263

¹H-NMR (CDCl₃) δ ppm: 0.8-1.0(m, 2H), 1.25(t, J=7Hz, 3H), 1.3-1.6(m,2H), 1.6-1.7(m, 1H), 1.9- 2.05(m, 4H), 2.1-2.2(m, 3H), 2.16(s, 3H),3.38(s, 2H), 3.52(s, 3H), 4.11(q, J=7Hz, 2H), 5.26(s, 2H), 6.91(dd, J=1,8Hz, 1H), 6.95(d, J=8Hz, 1H), 7.14(d, J=1Hz, 1H), # 7.83(s, 2H)

Examples

The following compounds were obtained by the same method as the one ofExample 8.

Ex. Structural formula MS M. p. NMR 1264

ESI (+) 400 (MH⁺) 210-212° C. ¹H-NMR (DMSO-d₆) δ ppm: 3.47(s, 2H),3.70(s, 2H), 6.76(dd, J=1, 8Hz, 1H), 6.79(s, 1H), 6.83(d, J=8Hz, 1H),7.29(s, 2H), 7.57(d, J=8Hz, 2H), 7.62(d, J=3Hz, 1H), 7.63(d, J=3Hz, 1H),7.75(d, J=8Hz, 2H), 9,47(s, 1H) 1265

ESI (+) 414 (MH⁺) 181-184° C. ¹H-NMR (DMSO-d₆) δ ppm: 2.50(s, 3H),3.31(s, 2H), 3.52(s, 2H), 6.74(d, J=8Hz, 1H), 6.80-6.88(m, 2H), 7.31(s,2H), 7.53(d, J=8Hz, 2H), 7.62(d, J=3Hz, 1H), 7.63(d, J=3Hz, 1H), 7.77(d,J=8Hz, 2H), 9.50(s, 1H) 1266

ESI (+) 379 (MH⁺) 241-244° C. ¹H-NMR (DMSO-d₆) δ ppm: 2.05(s, 3H),3.31(s, 2H), 3.51(s, 2H), 6.74(d, J=8Hz), 6.80-6.90(m, 2H), 7.45(d,J=8Hz, H), 7.62(d, J=2Hz, 1H), 7.63(d, J=2Hz, 1H), 7.89(d, J=8Hz, 2H),9.50(s, 1H) 1267

ESI (+) 385 (MH⁺) 203-204° C. ¹H-NMR (DMSO-d₆) δ ppm: 0.7-0.87(m, 2H),1.2- 1.35(m, 2H), 1.35-1.50(m, 1H), 1.75-1.90(m, 4H), 2.04(s, 3H),2.05(d, J=8Hz, 2H), 2.0-2.15(m, 1H), 3.21(s, 2H), 6.67(dd, J=1, 8Hz,1H), 6.75(d, J=1Hz, 1H), 6.81(d, J=8Hz, 1H), # 7.61(d, J=3Hz, 1H),7.62(d, J=3Hz, 1H), 9.48(s, 1H)

Examples

The following compounds were obtained by treating the compounds obtainedin Examples 1259 and 1260 by the same method as the one of Example 18.

Ex. Structural formula MS M. p. NMR 1268

ESI (+) 365 (MH⁺) 245-248° C. ¹H-NMR (DMSO-d₆) δ ppm: 3.54(s, 2H),3.75(s, 2H), 6.77(d, J=8Hz, 1H), 6.78(s, 1H), 6.84(d, J=8Hz, 1H),7.46(d, J=8Hz, 2H), 7.56- 7.68(m, 2H), 7.88(d, J=8Hz, 2H), 9.50(s, 1H)1269

ESI (+) 371 (M⁺) 217-220° C. ¹H-NMR (DMSO-d₆) δ ppm: 0.8-0.96(m, 2H),1.14- 1.32(m, 2H), 1.32-1.48(m, 1H), 1.70-1.86(m, 2H), 1.74-1.92(m, 2H),2.02- 2.16(m, 1H), 2.40(d, J=7Hz, 2H), 3.61(s, 2H), 6.75(s, 1H), 6.78(d,J=8Hz, 1H), 6.85(d, J=8Hz, 1H), 7.56- # 7.68(m, 2H), 9.53(s, 1H)

Examples

Similar to Example 1244,8-(N-methyl)aminomethyl-10H-pyrazino[2,3-b][1,4]benzothiazine wastreated with various alkyl halides to thereby give the followingcompounds.

Ex. Structural formula NMR 1270

¹H-NMR (CDCl₃) δ ppm: 1.25(t, J=7Hz, 3H), 1.30- 1.40(m, 2H),1.45-1.60(m, 2H), 1.60-1.75(m, 2H), 2.18(s, 3H), 2.30(t, J=7Hz, 2H),2.60-2.80(m, 2H), 3.41(s, 2H), 3.53(s, 3H), 4.12(q, J=7Hz, 2H), 5.29(s,2H), 6.90-6.96(m, 1H), 6.96(d, J=8Hz, 1H), 7.10(s, 1H), 7.83(d, # J=3Hz,1H), 7.84(d, J=3Hz, 1H) 1271

¹H-NMR (CDCl₃) δ ppm: 1.17(s, 6H), 1.36-1.48(m, 2H), 1.64-1.70(m, 2H),2.15(s, 3H), 2.32(t, J=7Hz, 2H), 3.39(s, 2H), 3.53(s, 3H), 3.64(s, 3H),5.28(s, 2H), 6.92(dd, J=1, 8Hz, 1H), 6.96(d, J=8Hz, 1H), 7.09(d, J=1Hz,1H), 7.82(d, J=3Hz, 1H), 7.83(d, J=3Hz, 1H) 1272

¹H-NMR (CDCl₃) δ ppm: 1.18(s, 6H), 1.77(t, J=7Hz, 2H), 2.16(s, 3H),2.34(t, J=7Hz, 2H), 3.40(s, 2H), 3.53(s, 3H), 3.62(s, 3H), 5.31(s, 2H),6.90-6.96(m, 1H), 6.96(d, J=8Hz, 1H), 7.07(s, 1H), 7.80-7.86(m, 2H)

Examples

The following compounds were obtained by treating the compounds obtainedin the above table successively by the same methods as those of Examples18 and 8.

Ex. Structural formula MS M. p. NMR 1273

ESI (+) 359 (MH⁺) 191-193° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.20-1.30(m, 2H),1.36- 1.54(m, 4H), 2.06(s, 3H), 2.18(t, J=7Hz, 2H), 2.26(t, J=7Hz, 2H),3.25(s, 2H), 6.68(dd, J=2, 8Hz, 1H), 6.74(d, J=2Hz, 1H), 6.81(d, J=8Hz,1H), 7.61(d, J=3Hz, 1H), 7.62(d, J=3Hz, 1H), # 9.44(s, 1H) 1274

ESI (+) 373 (MH⁺) 200-202° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.06(s, 6H),1.3-1.46(m, 4H), 2.05(s, 3H), 2.24- 2.32(m, 2H), 3.26(s, 2H), 6.69(d,J=8Hz, 1H), 6.73(s, 1H), 6.83(d, J=8Hz, 1H), 7.61(d, J=3Hz, 1H), 7.62(d,J=3Hz, 1H), 9.46(s, 1H) 1275

FAB (+) 359 (MH⁺) ¹H-NMR (CDCl₃) δ ppm: 1.21(s, 6H), 1.72-1.84(m, 2H),2.36(s, 3H), 2.68- 2.84(m, 2H), 3.56(br.s, 2H), 6.65-6.82(m, 3H),7.56(d, J=2.8Hz, 1H), 7.65(d, J=2.8Hz, 1H)

Example 1276N-Methyl-2-[[N-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-N-methyl]amino]ethanesulfonamide

The title compound was obtained as yellow crystals by treating8-chloromethyl-10H-pyrazino[2,3-b][1,4]benzothiazine withN-methyl-2-aminoethanesulfonamide in the presence of sodium bicarbonateby the same method as the one of Example 1244.

¹H-NMR(DMSO-d6) δ ppm: 2.13(s, 3H), 2.54(d, J=5 Hz, 3H), 2.64-2.70(m,2H), 3.14-3.20(m, 2H), 3.32(s, 2H), 6.71(d, J=8 Hz, 1H), 6.73(s, 1H),6.84(d, J=8 Hz, 1H), 6.80-6.90(m, 1H), 7.56-7.66(m, 2H), 9.45(s, 1H)

MS: ESI(+)366(MH⁺)

m.p.: 143-146° C.

Examples

The following compounds were obtained by treating(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbaldehydesuccessively by the same methods as those of Examples 900 and 9.

Ex. Structural formula MS M. p. NMR 1277

¹H-NMR (DMSO-d₆) δ ppm: 1.90(br.s, 1H), 2.66(t, J=7Hz, 2H), 3.30(s, 2H),3.50(t, J=7Hz, 2H), 3.65(br.s, 1H), 6.75(s, 1H), 6.79(d, J=8Hz, 1H),6.87(d, J=8Hz, 1H), 7.62(s, 2H), 9.56(br.s, 1H) 1278

¹H-NMR (DMSO-d₆) δ ppm: 1.42(m, 2H), 1.53(m, 2H), 2.73(t, J=6Hz, 2H),3.35(t, J=6Hz, 2H), 3.35(br.s, 2H), 3.76(s, 2H), 6.75(s, 1H), 6.84(d,J=8Hz, 1H), 6.92(d, J=8Hz, 1H), 7.63(d, J=3Hz, 1H), 7.66(d, J=3Hz, 1H),9.63(s, 1H) 1279

FAB (+) 302 (MH⁺) Hygro- scopic ¹H-NMR (DMSO-d₆) δ ppm: 2.78(s, 6H),3.37(br.s, 2H), 3.50(br.s, 2H), 4.02(s, 2H), 6.81(s, 1H), 6.95(d, J=8Hz,1H), 7.08(d, J=8Hz, 1H), 7.65(d, J=3Hz, 1H), 7.66(d, J=3Hz, 1H), 9.78(s,1H), 9.91(br.s, 2H), 11.14(br.s, 1H)

Examples

The following compounds were obtained from(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbaldehydeby the same method as the one of Example 900.

Ex. Structural formula NMR 1280

¹H-NMR (CDCl₃) δ ppm: 1.24(t, J=7Hz, 3H), 3.44(s, 3H), 3.49(s, 2H),4.0-4.1(m, 1H), 4.12(q, J=7Hz, 2H), 4.27(s, 2H), 5.22(s, 2H),6.55-6.60(m, 2H), 6.97(s, 2H), 7.04- 7.12(m, 2H), 7.12(s, 1H), 7.83(d,J=3Hz, 1H), 7.84(d, J=3Hz, 1H) 1281

¹H-NMR (CDCl₃) δ ppm: 1.44(d, J=7Hz, 3H), 3.43(s, 3H), 3.55-3.70(m, 1H),3.64(s, 3H), 4.00- 4.10(m, 1H), 4.26(s, 2H), 5.22(s, 2H), 6.54-6.60(m,2H), 6.97(s, 2H), 7.06- 7.14(m, 2H), 7.12(s, 1H), 7.82(d, J=3Hz, 1H),7.84(d, J=3Hz, 1H)

Examples

The following compounds were obtained by treating the compounds obtainedin the above table successively by the same methods as those of Examples18 and 8.

Ex. Structural formula MS M. p. NMR 1282

FAB (+) 365 (MH⁺) 252-256° C. ¹H-NMR (DMSO-d₆) δ ppm: 3.21(s, 2H),4.05(s, 2H), 6.44(d, J=8.4Hz, 2H), 6.75(d, J=8.0Hz, 1H), 6.76(s, 1H),6.83(d, J=8.0Hz, 1H), 6.91(d, J=8.4Hz, 2H), 7.61(m, 2H), 9.49(s, 1H)1283

228-233° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.26(d, J=8.0Hz, 3H), 3.40- 3.60(m,1H), 4.10(s, 2H), 6.58-6.70(m, 2H), 6.76(s, 1H), 6.77(d, J=8.0Hz, 1H),6.85(d, J=8.0Hz, 1H), 7.02(d, J=8.0Hz, 2H), 7.61(d, J=2.8Hz, 1H),7.62(d, J=2.8Hz, 1H), 9.52(s, 1H)

Example 12848-Aminomethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine

To a solution of 1.3 g ofN-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)phthalimidein 20 ml of ethanol was added 5 ml of hydrazine monohydrate and theresulting mixture was heated to 60° C. for 10 minutes. After distillingoff the solvent under reduced pressure, the residue was distributed intoa 5% aqueous solution of sodium hydroxide and ethyl acetate. The organiclayer was extracted and the extract was dried over potassium carbonate.After distilling off the solvent under reduced pressure, the obtainedresidue was purified by silica gel column chromatography (eluted withdichloromethane/methanol/aqueous ammonia) to thereby give 890 mg of thetitle compound as a yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 3.53(s, 3H), 3.80(s, 2H), 5.28(s, 2H), 6.92(dd,J=1.5, 8.0 Hz, 1H), 6.96(d, J=8.0 Hz, 1H), 7.10(d, J=1.5 Hz, 1H),7.81(d, J=2.8 Hz, 1H), 7.83(d, J=2.8 Hz, 1H)

Example 1285N-(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)formamide

250 mg of8-aminomethyl-10-methoxymethyl-10H-pyrazino-[2,3-b][1,4]benzothiazinewas heated under reflux in 10 ml of ethyl formate for 3 hours. Then thereaction mixture was brought back to room temperature and distributedinto an aqueous solution of ammonium chloride and ethyl acetate. Theorganic layer was extracted, washed with water and then dried overanhydrous sodium sulfate. After distilling off the solvent under reducedpressure, the crystals thus precipitated were filtered after addingdiisopropyl ether. Thus 230 mg of the title compound was obtained asyellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 3.37(s, 3H), 4.22(d, J=6.0 Hz, 2H), 5.22(s, 2H),6.91(dd, J=1.4, 8.0 Hz, 1H), 7.03(d, J=1.4 Hz, 1H), 7.07(d, J=8.0 Hz,1H), 7.92(d, J=2.8 Hz, 1H), 7.96(d, J=2.8 Hz, 1H), 8.12(s, 1H),8.51(br.t, J=6.0 Hz, 1H)

Example 1286N-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)formamide

75 mg of the title compound was obtained as yellow crystals by treating150 mg ofN-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)formamideby the same method as the one of Example 9.

¹H-NMR(DMSO-d₆) δ ppm: 4.10(d, J=6.0 Hz, 2H), 6.67(s, 1H), 6.68(d, J=7.7Hz, 1H), 6.86(d, J=7.7 Hz, 1H), 7.63(br.s, 2H), 8.10(br.s, 1H),8.73-8.53(br.t, J=6.0 Hz, 1H), 9.50(s, 1H)

Example 1287N-(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)acetamide

1 ml of acetic anhydride was added to 5 ml of a solution of 350 mg of8-aminomethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine indichloromethane and the resulting mixture was stirred at roomtemperature for 2 hours. After adding diethyl ether, the precipitatethus formed was taken up by filtration to thereby give 350 mg of thetitle compound as yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 1.86(s, 3H), 3.36(s, 3H), 4.16(d, J=5.9 Hz, 2H),5.21(s, 2H), 6.89(dd, J=1.6, 7.9 Hz, 1H), 7.00(d, J=1.6 Hz, 1H), 7.06(d,J=7.9 Hz, 1H), 7.92(d, J=2.6 Hz, 1H), 7.96(d, J=2.6 Hz, 1H), 8.36(t,J=5.9 Hz, 1H)

Example 1288N-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)acetamide

150 mg of the title compound was obtained by treating 250 mg ofN-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)acetamideby the same method as the one of Example 9.

¹H-NMR(DMSO-d₆) δ ppm: 1.84(s, 3H), 4.04(d, J=6.2 Hz, 2H), 6.65(s, 1H),6.66(d, J=8.4 Hz, 1H), 6.84(d, J=8.4 Hz, 1H), 7.52(d, J=3.2 Hz, 1H),7.53(d, J=3.2 Hz, 1H), 8.29(t, J=6.2 Hz, 1H), 9.49(s, 1H)

Examples

The following compounds were obtained by treating8-aminomethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazinesuccessively by the same methods as those of Examples 1287 and 434.

Ex. Structural formula MS M.p. NMR 1289

ooi ooi ¹H-NMR(DMSO-d₆) δ ppm: 1.25(t, J=7.3Hz, 3H), 4.12(d, J=6.3Hz,2H), 4.22(q, J=7.3Hz, 2H), 6.67(s, 1H), 6.68(d, J=7.4Hz, 1H), 6.85(d,J=7.4Hz, 1H), 7.62(d, J=3.1Hz, 1H), 7.63(d, J=3.1Hz, 1H), 9.40(t,J=6.3Hz, 1H), 9.51(s, 1H) 1290

¹H-NMR(DMSO-d₆) δ ppm: 4.28(d, J=6.0Hz, 2H), 6.73(d, J=7.8Hz, 1H),6.74(s, 1H), 6.85(d, J=7.8Hz, 1H), 7.45(t, J=7.7Hz, 2H), 7.52(t,J=7.7Hz, 1H), 7.61(s, 2H), 7.87(t, J=7.7Hz, 2H), 8.97(t, J=6.0Hz, 1H),9.50(s, 1H)

Examples

The following compounds were obtained by treating8-aminomethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazinesuccessively by the same methods as those of Examples 1287 and 8.

Ex. Structural formula MS M.p. NMR 1291

FAB (+) 336 (MH⁺) 249-253° C. (decompose) ¹H-NMR(DMSO-d₆) δ ppm: 4.33(d,J=5.9Hz, 2H), 6.72-6.79(m, 2H), 6.88(d, J=8.8Hz, 1H), 7.64(d, J=2.9Hz,1H), 7.65(d, J=2.9Hz, 1H), 7.80(m, 2H), 8.76(m, 2H), 9.31(t, J=5.9Hz,1H), 9.53(s, 1H) 1292

FAB (+) 336 (MH⁺) 243-245° C. (decompose) ¹H-NMR(DMSO-d₆) δ ppm: 4.33(d,J=5.9Hz, 2H), 6.75-6.80(m, 2H), 6.88(d, J=8.4Hz, 1H), 7.54(m, 1H),7.64(d, J=2.9Hz, 1H), 7.64(d, J=2.9Hz, 1H), 8.23(m, 1H), 8.73(m, 1H),9.06(m, 1H, 9.21(t, J=5.9Hz, 1H,) 9.53(s, 1H)

Example 1293N-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-1-methylpiperidine-4-carboxamide

The title compound was obtained as yellow crystals by treating8-aminomethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]-benzothiazineand 1-methylpiperidine-4-carboxylic acid successively by the samemethods as those of Examples 1303 and 8.

¹H-NMR(CDCl₃) δ ppm: 1.71-1.98(m, 5H), 2.04-2.18(m, 2H), 2.26(s, 3H),2.86-2.94(m, 2H), 4.26(d, J=5.9 Hz, 2H), 5.99(d, J=5.9 Hz, 1H), 6.43(d,J=1.6 Hz, 1H), 6.67(dd, J=1.6, 7.9 Hz, 1H), 6.79(d, J=7.9 Hz, 1H),7.01(s, 1H), 7.56(d, J=2.9 Hz, 1H), 7.67(d, J=2.9 Hz, 1H)

MS: FAB(+)336(MH⁺)

m.p.: 230-232° C. (decompose)

Example 1294N-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-5-methyl-1,2-oxazole-4-carboxamide

A solution of 520 mg of 5-methyl-1,2-oxazole-4-carboxylic acid and 0.75ml of triethylamine in tetrahydrofuran (10 ml) was ice-cooled. Afteradding 0.8 ml of diethyl chlorophosphate, the resulting mixture wasstirred at room temperature for 30 minutes. To the reaction mixture wasadded 5 ml of a solution of 750 mg of8-aminomethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]-benzothiazine intetrahydrofuran and the resulting mixture was stirred at roomtemperature for 1.5 hours. Next, the reaction mixture was distributedinto ethyl acetate and an aqueous solution of ammonium chloride. Theorganic layer was extracted, washed with water and dried over anhydroussodium sulfate. After distilling off the solvent under reduced pressure,the residue was purified by silica gel column chromatography (elutedwith dichloromethane/methanol) to thereby give 520 mg ofN-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-5-methyl-1,2-oxazole-4-carboxamide.Further, the product was treated by the same method as the one ofExample 434 to thereby give 310 mg of the title compound as yellowcrystals.

¹H-NMR(DMSO-d₆) δ ppm: 2.63(s, 3H), 4.23(d, J=6.3 Hz, 2H), 6.71(s, 1H),6.72(d, J=7.5 Hz, 1H), 6.86(d, J=7.5 Hz, 1H), 7.62(s, 2H), 8.79(t, J=6.3Hz, 1H), 8.89(s, 1H), 9.50(s, 1H)

Example 1295N-(1H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-2-cyano-3-oxobutanamide

120 mg of the title compound was obtained as yellow crystals by treating170 mg ofN-(10H-pyrazino[2,3-b][1,4]-benzothiazin-8-ylmethyl)-5-methyl-1,2-oxazole-4-carboxamidewith 0.17 ml of dimethylformamide dimethyl acetal by the same method asthe one of Example 505.

¹H-NMR(DMSO-d₆) δ ppm: 2.05(s, 3H), 4.13(s, 2H), 6.64-6.68(m, 2H),6.83(dd, J=2, 8 Hz, 1H), 7.61-7.63(m, 2H), 9.51(s, 1H)

MS: FAB(+)339(M⁺)

Example 1296(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)acetamide

200 mg of(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]-benzothiazin-8-ylmethyl)acetonitrilewas dissolved in 5 ml of dimethyl sulfoxide. After adding 200 mg ofpowdered potassium hydroxide, the resulting mixture was heated to 40 to60° C. for 10 minutes. Then the reaction mixture was distributed into 1N hydrochloric acid and ethyl acetate. The organic layer was extracted,washed successively with a saturated aqueous solution of sodiumbicarbonate and water and dried over anhydrous magnesium sulfate. Afterdistilling off the solvent under reduced pressure, the residue waspurified by silica gel column chromatography (eluted withdichloromethane/methanol) to thereby give 35 mg of the title compound asyellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 3.31(s, 2H), 3.38(s, 3H), 5.22(s, 2H),6.87-6.95(br.s, 1H), 6.91(dd, J=1.7, 8.0 Hz, 1H), 7.03(d, J=1.7 Hz, 1H),7.04(d, J=8.0 Hz, 1H), 7.42-7.50(br.s, 1H), 7.92(d, J=2.8 Hz, 1H),7.96(d, J=2.8 Hz, 1H)

Example 1297 (10H-Pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetamide

The title compound was obtained by treating(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetamide bythe same method as the one of Example 9.

¹H-NMR(DMSO-d₆) δ ppm: 3.18(s, 2H), 6.66(s, 1H), 6.67(d, J=7.6 Hz, 1H),6.82(d, J=7.6 Hz, 1H), 6.83-6.95(br.s, 1H), 7.37-7.48(br.s, 1H), 7.61(d,J=2.6 Hz, 1H), 7.63(d, J=2.6 Hz, 1H), 9.50(s, 1H)

Example 12983-[(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetamido]propanoic acid

The title compound was obtained by treating(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetic acidsuccessively by the same methods as those of Examples 1294, 18 and 8.

¹H-NMR(DMSO-d₆) δ ppm:

2.36(t, 2H, J=6.8 Hz)3.20(s, 2H)3.21(t, 2H, J=6.8 Hz)6.64(s, 1H)6.65(d,1H, J=8.0 Hz)6.80(d, 1H, J=8.0 Hz)7.61(d, 1H, J=2.8 Hz)7.63(d, 1H, J=2.8Hz)9.48(s, 1H)

MS: FAB(+)331(MH⁺)

m.p.: 220-225° C.

Example 12998-Amino-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine

10 ml of an aqueous solution of 720 mg of sodium hydroxide wasice-cooled and 0.24 ml of bromine was dropped thereinto. After stirringfor 5 minutes, 900 mg of(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carboxamidewas added thereto at once and the resulting mixture was heated to 40 to60° C. for 15 minutes. Next, the reaction mixture was distributed intowater and ethyl acetate. After filtering off the insoluble mattersthrough celite, the organic layer was extracted, washed with water anddried over anhydrous sodium sulfate. After distilling off the solventunder reduced pressure, the residue was purified by silica gel columnchromatography (eluted with dichloromethane/methanol) to thereby give400 mg of the title compound as yellow crystals.

H-NMR(DMSO-d₆) δ ppm: 3.37(s, 3H), 5.14(s, 2H), 5.31(br.s, 2H), 6.25(dd,J=1.9, 8.1 Hz, 1H), 6.46(d, J=1.9 Hz, 1H), 6.72(d, J=8.1 Hz, 1H),7.88(d, J=2.5 Hz, 1H), 7.91(d, J=2.5 Hz, 1H)

Example 1300N-(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetamide

200 mg of 8-amino-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazinewas suspended in 10 ml of ethyl acetate. After adding 1 ml of aceticanhydride, the reaction mixture was subjected to ultrasonication. Thecrystals thus precipitated were filtered and washed with diethyl etherto thereby give 206 mg of the title compound as yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 2.01(s, 3H), 3.38(s, 3H), 5.17(s, 2H), 7.01(d,J=8.6 Hz, 1H), 7.31(d, J=1.8, 8.6 Hz, 1H), 7.44(d, J=1.8 Hz, 1H),7.91(d, J=2.6 Hz, 1H), 7.95(d, J=2.6 Hz, 1H), 10.02(s, 1H)

Examples

The following compounds were obtained by treating the compounds obtainedin Examples 1299 and 1300 by the same method as the one of Example 8.

Ex. Structural formula MS NMR 1301

FAB (+) 216 (M⁺) ¹H-NMR(DMSO-d₆) δ ppm: 5.14(br.s, 2H), 6.04(dd, J=1.9,8.2Hz, 1H), 6.07(d, J=1.9Hz, 1H), 6.52(d, J=8.2Hz, 1H), 7.58(d, J=2.8Hz,1H), 7.60(d, J=2.8Hz, 1H), 9.31(s, 1H) 1302

¹H-NMR(DMSO-d₆) δ ppm: 1.97(s, 3H), 6.80(d, J=8.5Hz, 1H,) 6.96(d, J=1.6,8.5Hz, 1H), 7.16(d, J=1.6Hz, 1H), 7.62(d, J=2.9Hz, 1H), 7.63(d, J=2.9Hz,1H), 9.57(s, 1H), 9.88(s, 1H)

Example 1303(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carboxamide

1.04 g of(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carboxylicacid was dissolved in a mixture of dichloromethane (20 ml) withtetrahydrofuran (20 ml) in a nitrogen atmosphere. Under ice-cooling,1.04 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochlorideand 200 mg of 1-hydroxybenzotriazole were added thereto and theresulting mixture was stirred at room temperature for 30 minutes. Afterblowing ammonia gas thereinto, the reaction mixture was distributed intoan aqueous solution of sodium bicarbonate and ethyl acetate. The organiclayer was extracted, washed with water and dried over anhydrous sodiumsulfate. After distilling off the solvent under reduced pressure, thecrystals thus precipitated were filtered. Further, the aqueous layer wasacidified and the starting materials were recovered. After repeating theabove-mentioned procedures, the title compound (620 mg in total) wasobtained as yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 3.38(s, 3H), 5.28(s, 2H), 7.19(d, J=8.4 Hz, 1H),7.40-7.46(br.s, 1H), 7.47(dd, J=1.8, 8.4 Hz, 1H), 7.56(d, J=1.8 Hz, 1H),7.93(d, J=2.8 Hz, 1H), 7.95-8.02(br.s, 1H), 7.97(d, J=2.8 Hz, 1H)

Example 1304

(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-yl)carboxamide

The title compound was obtained by treating(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carboxamideby the same method as the one of Example 9.

¹H-NMR(DMSO-d₆) δ ppm: 6.96(d, J=7.8 Hz, 1H), 7.21(s, 1H), 7.23(d, J=7.8Hz, 1H), 7.27-7.34(br.s, 1H), 7.64(d, J=2.7 Hz, 1H), 7.65(d, J=2.7 Hz,1H), 7.80-7.87(br.s, 1H), 9.59(s, 1H)

Examples

The following compounds were obtained by the same method as the one ofExample 1303.

Ex. Structural formula NMR 1305

¹H-NMR(DMSO-d₆) δ ppm: 3.40(s, 3H), 5.33(s, 2H), 7.09(t, J=8.4Hz, 1H),7.28(d, J=8.2Hz, 1H), 7.34(t, J=8.4Hz, 2H), 7.60(d, J=1.6Hz, 1H),7.60(dd, J=1.6, 8.2Hz, 1H), 7.73(d, J=8.4Hz, 2H), 7.95(d, J=2.5Hz, 1H),7.99(d, J=2.5Hz, 1H), 10.24(s, 1H) 1306

¹H-NMR(DMSO-d₆) δ ppm: 3.41(s, 3H), 5.36(s, 2H), 7.28(d, J=8.8Hz, 1H),7.29(d, J=3.7Hz, 1H), 7.55(d, J=3.7Hz, 1H), 7.70(dd, J=1.7, 8.8Hz, 1H),7.71(d, J=1.7Hz, 1H), 7.94(d, J=2.8Hz, 1H), 7.99(d, J=2.8Hz, 1H),12.65-12.75(br.s, 1H) 1307

¹H-NMR(DMSO-d₆) δ ppm: 1.09(t, J=6.5Hz, 3H), 3.25(dt, J=5.5, 6.5Hz, 2H),3.38(s, 3H), 5.28(s, 2H), 7.19(d, J=8.3Hz, 1H), 7.44(dd, J=1.5, 8.3Hz,1H), 7.53(d, J=1.5Hz, 1H), 7.93(d, J=2.7Hz, 1H), 7.97(d, J=2.7Hz, 1H),8.48(t, J=5.5Hz, 1H)

Examples

The following compounds were obtained by treating the compounds obtainedin the above table by the same method as the one of Example 434.

Ex. Structural formula MS M.p. NMR 1308

281- 282° C. ¹H-NMR(DMSO-d₆) δ ppm: 7.05(d, J=8.5Hz, 1H), 7.07(t,J=8.1Hz, 1H), 7.26(s, 1H), 7.31(d, J=8.5Hz, 1H), 7.33(t, J=8.1Hz, 2H),7.65(d, J=2.9Hz, 1H), 7.66(d, J=2.9Hz, 1H), 7.70(d, J=8.1Hz, 2H),9.66(s, 1H), 10.16(s, 1H) 1309

320- 322° C. ¹H-NMR(DMSO-d₆) δ ppm: 7.04(d, J=8.4Hz, 1H), 7.25(d,J=3.9Hz, 1H), 7.32(d, J=1.6Hz, 1H), 7.50(dd, J=1.6, 8.4Hz, 1H), 7.53(d,J=3.9Hz, 1H), 7.64(d, J=2.9Hz, 1H), 7.67(d, J=2.9Hz, 1H), 9.71(s, 1H),12.47-12.60(br.s, 1H) 1310

274- 275° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.06(t, J=7.0Hz, 3H), 3.21(dq,J=5.7, 7.0Hz, 2H), 6.96(d, J=8.3Hz, 1H), 7.18(dd, J=1.6, 8.3Hz, 1H),7.19(d, J=1.6Hz, 1H), 7.63(d, J=2.9Hz, 1H), 7.64(d, J=2.9Hz, 1H),8.35(t, J=5.7Hz, 1H), 9.59(s, 1H)

Examples

The following compounds were obtained by effectingdehydration/condensation with various amines by the same method as theone of Example 1303 and treating the compounds thus obtained by the samemethod as the one of Example 9.

Ex. Structural formula MS NMR 1311

ESI (+) 328.0 (MH⁺) ¹H-NMR(DMSO-d₆) δ ppm: 2.80(s, 3H), 2.95-3.10(br.s,4H), 3.22-3.33(br.s, 4H), 6.78(d, J=2Hz, 1H), 6.84(dd, J=2, 8Hz, 1H),7.00(d, J=8Hz, 1H), 7.67(s, 2H), 9.66(s, 1H) 1312

FAB (+) 314 (MH⁺) ¹H-NMR(DMSO-d₆) δ ppm: 3.40-3.65(m, 8H), 6.75(d,J=1.7Hz, 1H), 6.78(dd, J=1.7, 7.7Hz, 1H), 6.96(d, J=7.7Hz, 1H), 7.65(s,2H, 9.60(s, 1H) 1313

¹H-NMR(DMSO-d₆) δ ppm: 1.17(t, J=7.4Hz, 3H), 4.28(q, J=7.4Hz, 2H),7.07(d, J=8.1Hz, 1H), 7.26(d, J=1.7Hz, 1H), 7.37(dd, J=1.7, 8.1Hz, 1H),7.65(d, J=2.8Hz, 1H), 7.88(d, J=8.7Hz, 2H), 7.93(d, J=8.7Hz, 2H),9.68(s, 1H), 10.47(s, 1H)

Example 13144-[(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-yl)carboxamido]-benzoic acid

The title compound was obtained by treating ethyl4-[(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carboxamido]benzoate bythe same method as the one of Example 18.

¹H-NMR(DMSO-d₆) δ ppm: 7.07(d, J=7.8 Hz, 1H), 7.26(d, J=1.8 Hz, 1H),7.37(dd, J=1.8, 7.8 Hz, 1H), 7.65(d, J=3.1 Hz, 1H), 7.67(d, J=3.1 Hz,1H), 7.85(d, J=9.1 Hz, 2H), 7.91(d, J=9.1 Hz, 2H), 9.68(s, 1H), 10.45(s,1H)

Examples

The following compounds were obtained by dehydrating/condensing(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetic acid with variousamines by the same method as the one of Example 1303.

Ex. Structural formula MS M.p. NMR 1315

FAB (+) 344 (MH⁺) 145- 148° C. ¹H-NMR(CDCl₃) δ ppm: 1.61(quint, J=6.0Hz,2H), 2.13(s, 6H), 2.34(t, J=6.0Hz, 2H), 3.33(m, 2H), 3.38(s, 2H),6.48(d, J=1.5Hz, 1H), 6.69(dd, J=1.5, 7.9Hz, 1H), 6.84(d, J=7.9Hz, 1H),7.01(br.s, 1H), 7.38(br.s, 1H), 7.58(d, J=2.9Hz, 1H), 7.69(d, J=2.9Hz,1H) 1316

FAB (+) 358 (MH⁺) ¹H-NMR(CDCl₃) δ ppm: 1.63-1.75(m, 2H), 2.20(s,6H),2.22, 2.26(t, J=7.1Hz, total2H), 2.94, 2.99(s, total3H), 3.34,3.41(t, J=7.1Hz, total2H), 3.54, 3.62(s, total2H), 6.51(d, J=1.8Hz, 1H),6.64(dd, J=1.8, 7.9Hz, 1H), 6.76, 6.77(d, J=7.9Hz, # total1H), 7.55(d,J=2.9Hz, 1H), 7.58, 7.64(br.s, total1H), 7.63(d, J=2.9Hz, 1H), 7.65(m,1H) 1317

FAB (+) 300 (M⁺) 212° C. (decom- pose) ¹H-NMR(CDCl₃) δ ppm: 0.88(t,J=7.5Hz, 3H), 1.49(m, 2H), 3.20(q, J=6.6Hz, 2H), 3.39(s, 2H), 5.54(m,1H), 6.45(d, J=1.5Hz, 1H), 6.69(dd, J=1.5, 7.7Hz, 1H), 6.84(d, J=7.7Hz,1H), 6.93(s, 1H), 7.57(d, J=2.9Hz, 1H), 7.69(d, J=2.9Hz, 1H)

Example 1318(E)-N,N-Pentamethylene-3-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)propenamide

140 mg of the title compound was obtained as yellow crystals from 273 mgof(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carboxamideby the same method as the one of Production Example 25.

¹H-NMR(CDCl₃) δ ppm: 1.56-1.66(m, 4H), 1.66-1.74(m, 2H), 3.52-3.63(m,2H), 3.54(s, 3H), 3.63-3.72(m, 2H), 5.28(s, 2H), 6.85(d, J=15.3 Hz, 1H),7.00(d, J=7.8 Hz, 1H), 7.16(dd, J=1.6, 7.8 Hz, 1H), 7.24(d, J=1.6 Hz,1H), 7.55(d, J=15.3 Hz, 1H), 7.85(s, 2H)

Example 1319(E)-3-(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)propenoicacid

The title compound was obtained as yellow crystals by treating ethyl(E)-3-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)propenoateby the same method as the one of Example 18.

¹H-NMR(DMSO-d₆) δ ppm: 3.38(s, 3H), 5.33(s, 2H), 6.48(d, J=15.8 Hz, 1H),7.16(d, J=7.9 Hz, 1H), 7.32(s, 1H), 7.34(d, J=7.9 Hz, 1H), 7.50(d,J=15.8 Hz, 1H), 7.93(d, J=2.4 Hz, 1H), 7.97(d, J=2.4 Hz, 1H),12.4-12.5(br.s, 1H)

Example 13203-(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)propenamide

950 mg of(E)-3-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)propenoicacid was dissolved in a solvent mixture of tetrahydrofuran (10 ml) withN,N-dimethylformamide (10 ml) in a nitrogen atmosphere. Underice-cooling, 0.48 ml of diethyl chlorophosphonate was dropped into thereaction mixture. After stirring at room temperature for 30 minutes,ammonia gas was blown into the system. Then the reaction mixture wasdistributed into an aqueous solution of sodium carbonate and ethylacetate and extracted with ethyl acetate. The extract was washed withwater and dried over anhydrous sodium sulfate. After distilling off thesolvent under reduced pressure, the crystals thus precipitated wererecrystallized from diisopropyl ether/ethyl acetate to thereby give 400mg of the title compound as yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 3.41(s, 3H), 5.30(s, 2H), 6.54(d, J=16.0 Hz, 1H),7.12(br.s, 1H), 7.15(d, J=7.9 Hz, 1H), 7.20(dd, J=1.3, 7.9 Hz, 1H),7.26(d, J=1.3 Hz, 1H), 7.33(d, J=16.0 Hz, 1H), 7.59(br.s, 1H), 7.93(d,J=2.4 Hz, 1H), 7.97(d, J=2.4 Hz, 1H)

Examples

The following compounds were obtained by treating the compounds obtainedin Examples 1318 and 1320 by the same method as the one of Example 9.

Ex. Structural formula NMR 1321

¹H-NMR(DMSO-d₆) δ ppm: 1.40-1.55(m, 4H), 1.55-1.64(m, 2H), 3.46-3.54(m,2H), 3.54-3.63(m, 2H), 6.91(s, 1H), 6.93(d, J=8.3Hz, 1H), 7.05(d,J=15.1Hz, 1H), 7.19(d, J=8.3Hz, 1H), 7.21(d, J=15.1Hz, 1H), 7.63(d,J=3.0Hz, 1H), 7.65(d, J=3.0Hz, 1H), 9.46(s, 1H) 1322

¹H-NMR(DMSO-d₆) δ ppm: 6.41(d, J=15.3Hz, 1H), 6.89(s, 1H), 6.93(d,J=8.4Hz, 1H), 6.96(d, J=8.4Hz, 1H), 7.12(br.s, 1H), 7.18(d, J=15.3Hz,1H), 7.60(br.s, 1H), 7.63-7.67(m, 2H), 9.61(s, 1H)

Example 1323(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)thioacetamide

The title compound was obtained by treating(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetonitrileby the same method as the one of Example 1533.

¹H-NMR(CDCl₃) δ ppm: 3.53(s, 3H), 4.01(s, 2H), 5.25(s, 2H), 6.86(br.s,1H), 6.88(dd, J=1.7, 7.7 Hz, 1H), 7.00(d, J=7.7 Hz, 1H), 7.05(d, J=1.7Hz, 1H), 7.73-7.85(br.s, 1H), 7.85(d, J=2.9 Hz, 1H), 7.86(d, J=2.9 Hz,1H)

Examples

The following compounds were obtained by treating(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbonitrilesuccessively by the same methods as those of Examples 1339-1 and 9.

Ex. Structural formula MS NMR 1324

FAB (+) 274 (M⁺) ¹H-NMR(DMSO-d₆) δ ppm: 3.61(s, 2H), 6.73(d, J=1.7Hz,1H), 6.74(dd, J=1.7, 7.7Hz, 1H), 6.83(d, J=7.7Hz, 1H), 7.62(d, J=2.8Hz,1H), 7.63(d, J=2.8Hz, 1H), 9.29-9.35(br.s, 1H), 9.47-9.54(br.s, 1H),9.53(s, 1H) 1325

FAB (+) 260 (M⁺) ¹H-NMR(DMSO-d₆) δ ppm: 6.93(d, J=7.8Hz, 1H), 7.13(d,J=7.8Hz, 1H), 7.32(s, 1H), 7.64(br.s, 2H), 9.40(br.s, 1H), 9.61(s, 1H),9.80(br.s, 1H)

Examples

The following compounds were obtained by treating8-aminomethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine bythe same method as the one of Example 316.

Ex. Structural formula NMR 1326

¹H-NMR(CDCl₃) δ ppm: 2.93(s, 3H), 3.54(s, 3H), 4.23(d, J=6.0Hz, 2H),4.76(br.t, J=6.0Hz, 1H), 5.26(s, 2H), 6.95(dd, J=1.7, 7.6Hz, 1H),7.00(d, J=7.6Hz, 1H), 7.13(d, J=1.7Hz, 1H), 7.84(d, J=2.7Hz, 1H),7.86(d, J=2.7Hz, 1H) 1327

¹H-NMR(CDCl₃) δ ppm: 3.53(s, 3H), 4.33(d, J=6.0Hz, 2H), 5.22(s, 2H),5.64-5.74(br.d, J=6.0Hz, 1H), 6.78(dd, J=1.7, 8.0Hz, 1H), 6.96(d,J=8.0Hz, 1H), 7.03(d, J=1.7Hz, 1H), 7.87(d, J=3.0Hz, 1H), 7.88(d,J=3.0Hz, 1H)

Examples

The following compounds were obtained by treating8-aminomethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]-benzothiazinesuccessively by the same methods as those of Examples 316 and 434.

Ex. Structural formula MS NMR 1328

FAB (+) 370 (M⁺), 371 (MH⁺) ¹H-NMR(DMSO-d₆) δ ppm: 3.76(d, J=6.4Hz, 2H),6.62(d, J=7.3Hz, 1H), 6.69(s, 1H), 6.80(d, J=7.3Hz, 1H), 7.57(t,J=8.0Hz, 2H), 7.61(t, J=8.0Hz, 1H), 7.53(s, 2H), 7.77(d, J=8.0Hz, 2H),8.11(d, J=6.4Hz, 1H), 9.52(s, 1H) 1329

¹H-NMR(DMSO-d₆) δ ppm: 2.86(s, 3H), 3.95(d, J=6.2Hz, 2H), 6.74(d,J=8.3Hz, 1H), 6.75(s, 1H), 6.87(d, J=8.3Hz, 1H), 7.50(t, J=6.2Hz, 1H),7.62(d, J=2.8Hz, 1H), 7.63(d, J=2.8Hz, 1H), 9.54(s, 1H) 1330

¹H-NMR(DMSO-d₆) δ ppm: 4.15(s, 2H), 6.73(d, J=8.6Hz, 1H), 6.74(s, 1H),6.91(d, J=8.6Hz, 1H), 7.63(d, J=2.8Hz, 1H), 7.65(d, J=2.8Hz, 1H),9.62(s, 1H), 9.87-9.96(br.s, 1H)

Example 1331N-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)sulfamide

5 ml of a solution of 283 mg of chlorosulfonyl isocyanate intetrahydrofuran was ice-cooled and 92 mg of formic acid was addedthereto. After stirring at room temperature for 30 minutes, the mixturewas added to a solution of 276 mg of8-aminomethyl-10H-pyrazino[2,3-b][1,4]benzothiazine in tetrahydrofuran(5 ml) and the resulting mixture was stirred at room temperature for 20minutes. Next, it was distributed into an aqueous solution of potassiumcarbonate and ethyl acetate and the aqueous layer was extracted. Theaqueous layer was well washed with ethyl acetate and the organic solventcontained therein was distilled off under reduced pressure. The residualaqueous solution was purified by High-porous gel chromatography (CHP20Pmfd. by Mitsubishi Chemical Industries, Ltd., 75-150 μ) (eluted withwater/methanol) to thereby give 45 mg of the title compound as yellowcrystals.

¹H-NMR(DMSO-d₆) δ ppm: 3.70(d, J=7.0 Hz, 2H), 4.57(t, J=7.0 Hz, 1H),6.73(d, J=8.0 Hz, 1H), 6.74(s, 1H), 6.78(d, J=8.0 Hz, 1H), 7.57-7.64(m,2H), 9.46(s, 1H)

MS: FAB(−)309(M⁻)

Example 1332N-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)phenylcarbamate

Into a solution of 350 mg of8-aminomethyl-10H-pyrazino[2,3-b][1,4]benzothiazine and 100 mg ofpyridine in tetrahydrofuran (8 ml) was dropped 270 mg of phenylchlorocarbonate and the resulting mixture was stirred for 5 minutes.Then the reaction mixture was distributed into water and ethyl acetate.The organic layer was extracted, washed with water and dried overanhydrous sodium sulfate. After distilling off the solvent under reducedpressure, diisopropyl ether was added to the crystals thus precipitatedfollowed by filtration. Thus, 230 mg of the title compound was obtainedas yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 4.08(d, J=5.9 Hz, 2H), 6.72(d, J=8.6 Hz, 1H),6.73(s, 1H), 6.88(d, J=8.6 Hz, 1H), 7.11(d, J=7.8 Hz, 2H), 7.19(t, J=7.8Hz, 1H), 7.37(t, J=7.8 Hz, 2H), 7.62-7.65(m, 2H), 8.25(t, J=5.9 Hz, 1H), 9.57(s, 1H)

Examples

The following compounds were obtained by treating(10-methoxymethyl-10H-pyrazino[2,3-b](1,4]benzothiazin-8-yl)methanolsuccessively by the same methods as those of Examples 1336 and 9.

Ex. Structural formula MS M.p. NMR 1333

FAB (+) 330 (M⁺) 169- 171° C. ¹H-NMR(CDCl₃) δ ppm: 0.93(t, J=6Hz, 3H),1.30-1.40(m, 2H), 1.40-1.50(m, 2H), 3.10-3.22(m, 2H), 4.70-4.80(br.s,1H), 4.92(s, 2H), 6.40-6.50(br.s, 1H), 6.53(s, 1H), 6.82(d, J=8Hz, 1H),6.88(d, J=8Hz, 1H), 7.58(d, J=2Hz, 1H) 7.80(d, J=2Hz, 1H) 1334

FAB (+) 350 (M⁺) 237- 240° C. ¹H-NMR(DMSO-d₆) δ ppm: 4.93(s, 2H),6.80(d, J=8Hz, 1H), 6.86(s, 1H), 6.92(d, J=8Hz, 1H), 6.93-6.99(m, 1H),7.22-7.28(m, 2H), 7.41-7.48(m, 2H), 7.62(d, J=2Hz, 2H), 9.58(s, 1H),9.77(br.s, 1H)

Example 1335 N-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)urea

A solution of 420 mg of8-aminomethyl-10H-pyrazino[2,3-b][1,4]benzothiazine in acetic acid (2ml)/water (4 ml) was heated to 70° C. and potassium cyanate (1 g intotal) was added thereto over 2 hours. Then the reaction mixture wasbrought back to room temperature and diluted with water. The solid thusprecipitated was filtered, washed well with water and recrystallizedfrom dimethyl sulfoxide/ethyl acetate to thereby give 70 mg of the titlecompound as yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 3.97(d, J=6.4 Hz, 2H), 5.52(s, 2H), 6.33(t, J=6.4Hz, 1H), 6.66(d, J=8.7 Hz, 1H), 6.67(s, 1H), 6.83(d, J=8.7 Hz, 1H),7.62(d, J=2.5 Hz, 1H), 7.63(d, J=2.5 Hz, 1H), 9.52(s, 1H)

MS: FAB(+)273(M⁺)

Example 1336N-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-N′-phenylurea

To 5 ml of a solution of 200 mg of8-aminomethyl-10H-pyrazinot[2,3-b][1,4]benzothiazine in tetrahydrofuranwas added 120 mg of phenyl isocyanate and the resulting mixture wasstirred at room temperature for 1 hour. The crystals thus precipitatedwere filtered after adding diethyl ether thereto and thus the titlecompound was obtained as yellow crystals almost quantitatively.

¹H-NMR(DMSO-d₆) δ ppm: 4.10(d, J=5.8 Hz, 2H), 6.53(t, J=5.8 Hz, 1H),6.70(d, J=7.9 Hz, 1H), 6.71(s, 1H), 6.85(d, J=7.9 Hz, 1H), 6.88(t, J=8.1Hz, 1H), 7.20(t, J=8.1 Hz, 2H), 7.38(d, J=8.1 Hz, 2H), 7.62(s, 2H),8.54(s, 1H), 9.53(s, 1H)

Example 1337N-(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-N′-benzoylthiourea

To 5 ml of a solution of 350 mg of ammonium thiocyanate in acetone wasadded in a nitrogen atmosphere 0.50 ml of benzoyl chloride and theresulting mixture was heated under reflux for 5 minutes. Then 5 ml of asolution of 890 mg of8-aminomethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine inacetone was added thereto and the resulting mixture was heated underreflux for additional 1.5 hours. Next, the reaction mixture wasdistributed into water and ethyl acetate, washed with water and driedover anhydrous sodium sulfate. After distilling off the solvent underreduced pressure, the residue was purified by silica gel columnchromatography (eluted with n-hexane/ethyl acetate) and recrystallizedfrom diisopropyl ether to thereby give 710 mg of the title compound asyellow crystals.

¹H-NMR(CDCl₃) δ ppm: 3.53(s, 3H), 4.85(d, J=6 Hz, 2H), 5.28(s, 2H),7.01(s, 2H), 7.20(s, 1H), 7.52(t, J=8.0 Hz, 2H), 7.64(tt, J=1.3, 8.0 Hz,1H), 7.83(dd, J=1.3, 8.0 Hz, 2H), 7.84(d, J=2.9 Hz, 1H), 7.85(d, J=2.9Hz, 1H), 9.05(br.s, 1H), 10.98-11.07(br.s, 1H)

Example 1338N-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-N′-benzoylthiourea

250 mg of the title compound was obtained as yellow crystals by treating300 mg ofN-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-N′-benzoylthioureaby the same method as the one of Example 434.

¹H-NMR(CDCl₃) δ ppm: 5.77(d, J=6 Hz, 2H), 6.58(d, J=1.5 Hz, 1H),6.84(dd, J=1.5, 8.1 Hz, 1H), 6.87(d, J=8.1 Hz, 1H), 7.30-7.39(br.s, 1H),7.49(d, J=3.1 Hz, 1H), 7.53(t, J=7.7 Hz, 2H), 7.64(tt, J=1.0, 7.7 Hz,1H), 7.67(d, J=3.1 Hz, 1H), 7.84(dd, J=1.0, 7.7 Hz, 2H), 9.10(br.s, 1H),10.96-11.16(br.s, 1H)

Example 1339 N-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)thiourea

250 mg ofN-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-N′-benzoylthioureawas added to a mixture of a 20% aqueous solution of potassium hydroxide(5 ml) with methanol (5 ml). After further adding a small portion oftetrahydrofuran, the resulting mixture was heated to 50° C. for 5minutes. Then the reaction mixture was brought back to room temperatureand distributed into water and ethyl acetate. The organic layer wasextracted, washed with water and dried over anhydrous sodium sulfate.After distilling off the solvent under reduced pressure, the crystalsthus precipitated were suspended in ethyl acetate and filtered. Thus,140 mg of the title compound was obtained as yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 4.36-4.48(br.s, 2H), 6.68(br.s, 1H), 6.69(br.d,J=7.8 Hz, 1H), 6.85(d, J=7.8 Hz, 1H), 6.97-7.22(br.s, 2H), 7.62(d, J=3.2Hz, 1H), 7.64(d, J=3.2HZ, 1H), 7.85-7.95(br.s, 1H), 9.50-9.60(br.s, 1H)

MS: FAB(+)289(M⁺)

Examples

The following compounds were obtained by treating(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)methanolsuccessively by the same methods as those of Examples 788 and 9.

Ex. Structural formula MS M.p. NMR 1340

ESI(+) 246 (MH⁺) 189- 192° C. ¹H-NMR(CDCl₃)δppm: 3.37(s, 3H), 4.30(s,2H), 6.51(s, 1H), 6.52(s, 1H), 6.78(d, J=8Hz, 1H), 6.85(d, J=8Hz, 1H),7.57(d, J=3Hz, 1H), 7.68(d, J=3Hz, 1H) 1341

ESI(+) 322 (MH⁺) 118- 120° C. ¹H-NMR(CDCl₃)δppm: 4.40(s, 2H), 4.54(s,2H), 6.54(s, 1H), 6.60- 6.70(br.s, 1H), 6.59(d, J=8Hz, 1H), 6.85(d,J=8Hz, 1H), 7.22-7.45(m, 5H), 7.57(s, 1H), 7.67(s, 1H)

Example 1342(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbohydroxamicacid

To 2 ml of an aqueous solution of 280 mg of sodium hydroxide and 210 mgof hydroxylamine hydrochloride was added 5 ml of a solution of 303 mg ofmethyl(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carboxylatein tetrahydrofuran and the resulting mixture was stirred at roomtemperature for 1 hour. Then the reaction mixture was distributed intodilute hydrochloric acid and ethyl acetate. The organic layer wasextracted, washed with water and dried over anhydrous sodium sulfate.After distilling off the solvent under reduced pressure, the residue waspurified by silica gel column chromatography (eluted with n-hexane/ethylacetate) to thereby give 240 mg of the title compound as yellowcrystals.

¹H-NMR(CDCl₃) δ ppm: 3.38(s, 3H), 5.28(s, 2H), 7.18(d, J=8.0 Hz, 1H),7.32(dd, J=1.4, 8.0 Hz, 1H), 7.45(d, J=1.4 Hz, 1H), 7.93(d, J=3.1 Hz,1H), 7.97(d, J=3.1 Hz, 1H), 9.06(s, 1H), 11.23(br.s, 1H)

Example 1343 (10H-Pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbohydroxamicacid

40 mg of the title compound was obtained as yellow crystals by treating240 mg of(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbohydroxamicacid by the same method as the one of Example 434.

¹H-NMR(DMSO-d₆) δ ppm: 6.95(d, J=8.2 Hz, 1H), 7.06(dd, J=1.6, 8.2 Hz,1H), 7.14(d, J=1.6 Hz, 1H), 7.63(d, J=3.2 Hz, 1H), 7.65(d, J=3.2 Hz,1H), 9.00(br.s, 1H), 9.60(s, 1H), 11.05-11.17(br.s, 1H)

Example 1344N-(Methanesulfonyl)-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetamide

To a solution of 0.259 g of(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetic acid intetrahydrofuran (10 ml) was added in a nitrogen atmosphere 0.18 g ofcarbonyldiimidazole and the resulting mixture was heated under refluxfor 30 minutes. Then the reaction mixture was brought back to roomtemperature and 0.285 g of methanesulfonamide was added thereto. Afterstirring at room temperature for 16 hours, the solvent was distilled offunder reduced pressure and the residue was purified by silica gel columnchromatography (eluted with dichloromethane/methanol) to thereby give0.163 g of the title compound as a yellow solid.

¹H-NMR(DMSO-d₆) δ ppm: 3.10(s, 3H), 3.33(s, 2H), 6.65(s, 1H), 6.66(d,J=8 Hz, 1H), 6.83(d, J=8 Hz, 1H), 7.62(d, J=4 Hz, 1H), 7.63(d, J=4 Hz,1H), 9.52(s, 1H)

m.p.: 236-238° C.

MS: FAB(+)336(MH⁺)

Example 1345N-Cyano-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetamide

0.100 g of the title compound was obtained as a yellow solid by treating0.259 g of (10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetic acid by thesame method as the one of Example 1344 by using 0.126 g of cyanamide asa substitute for the methanesulfonamide.

¹H-NMR(DMSO-d₆) δ ppm: 3.37(s, 2H), 6.65(s, 1H), 6.67(d, J=8 Hz, 1H),6.93(d, J=8 Hz, 1H), 7.62(d, J=3 Hz, 1mH), 7.63(d, J=3 Hz, 1H), 9.51(s,1H)

MS: FAB(+)263(M⁺)

m.p.: 197-198° C.

Example 1346Sodium(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)methanesulfonate

To a solution of 900 mg of8-chloromethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine ina mixture of water (8 ml)/methanol (4 ml) was added 0.8 g of sodiumsulfite and the resulting mixture was heated to 90° C. for 2 hours. Thenthe reaction mixture was brought back to room temperature and dilutedwith ethanol. After filtering off the inorganic salt, silica gel wasadded to the filtrate. After distilling off the solvent under reducedpressure, the residue was purified by silica gel column chromatography(eluted with dichloromethane/methanol/acetic acid) to thereby give 650mg of the title compound as yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 3.37(s, 3H), 3.62(s, 2H), 5.20(s, 2H), 6.95(dd,J=1.2, 7.8 Hz, 1H)6.99(d, J=7.8 Hz, 1H), 7.09(d, J=1.2 Hz, 1H), 7.90(d,J=2.5 Hz, 1H), 7.95(d, J=2.5 Hz, 1H)

Example 1347Sodium(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)methane-sulfonate

200 mg of the title compound was obtained as yellow crystals by treating320 mg ofsodium(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)methanesulfonateby the same method as the one of Example 434.

¹H-NMR(DMSO-d₆) δ ppm: 3.49(s, 2H), 6.69(dd, J=1.6, 7.7 Hz, 1H), 6.74(d,J=1.6 Hz, 1H), 6.77(d, J=7.7 Hz, 1H), 7.60(d, J=2.9 Hz, 1H), 7.62(d,J=2.9 Hz, 1H), 9.47(s, 1H) MS: FAB(+)317(M⁺)

Example 13488-(Purin-9-ylmethyl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazineand8-(purin-7-ylmethyl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine

In accordance with the procedure of Example 1094, 740 mg of8-chloromethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazinewas reacted with 460 mg of purine in the presence of sodium hydride (60%oily) in N,N-dimethylformamide (10 ml). The two isomers thus obtainedwere purified by silica gel column chromatography (eluted withdichloromethane/methanol) to thereby give 320 mg of8-(purin-9-ylmethyl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazineand 125 mg of8-(purin-7-ylmethyl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazineeach as yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 3.24(s, 3H), 5.12(s, 2H), 5.46(s, 2H), 6.96(d,J=7.8 Hz, 1H), 7.07(s, 1H), 7.09(d, J=7.8 Hz, 1H), 7.91(d, J=2.8 Hz,1H), 7.94(d, J=2.8 Hz, 1H), 8.72(s, 1H), 8.94(s, 1H), 9.17(s, 1H)

¹H-NMR(DMSO-d₆) δ ppm: 3.26(s, 3H), 5.19(s, 2H), 5.56(s, 2H), 7.01(d,J=7.8 Hz, 1H), 7.09(s, 1H), 7.11(d, J=7.8 Hz, 1H), 7.91(d, J=2.8 Hz,1H), 7.94(d, J=2.8 Hz, 1H), 8.87(s, 1H), 8.96(s, 1H), 9.14(s, 1H)

Examples

The following compounds having substituents at different sites wereobtained by reacting8-chloromethyl-10-methoxymethyl-10H-pyrazino(2,3-b][1,4]benzothiazinewith various purines by the same method as the one of Example 1348.

Ex. Purine Structural formula NMR 1349

¹H-NMR(DMSO-d₆)δppm: 2.58(s, 3H), 3.12(s, 3H), 5.05(s, 2H), 5.68(s, 2H),6.70-6.75(m, 2H), 7.11(d, J=8Hz, 1H), 7.91(d, J=3Hz, 1H), 7.94(d, J=3Hz,1H), 8.75(s, 1H), 8.78(s, 1H) 1350

¹H-NMR(DMSO-d₆)δppm: 2.70(s, 3H), 3.25(s, 3H), 5.11(s, 2H), 5.42(s, 2H),6.93(dd, J=2, 8Hz, 1H), 7.06(d, J=2Hz, 1H), 7.07(d, J=8Hz, 1H), 7.90(d,J=3Hz, 1H), 7.94(d, J=3Hz, 1H), 8.62(s, 1H), 8.77(s, 1H) 1351

¹H-NMR(CDCl₃)δppm: 3.43(s, 3H), 3.42-3.65(br.s, 6H), 5.17(s, 2H),5.28(s, 2H), 6.82(dd, J=2, 8Hz, 1H), 6.96(d, J=8Hz, 1H), 7.08(d, J=2Hz,1H), 7.72(s, 1H), 7.83(d, J=3Hz, 1H), 7.84(d, J=3Hz, 1H), 8.38(s, 1H)1352

¹H-NMR(CDCl₃)δppm: 3.33(br.s, 3H), 3.43(s, 3H), 3.92(br.s, 3H), 5.17(s,2H), 5.44(s, 2H), 6.93(dd, J=2, 8Hz, 1H), 6.97(d, J=8Hz, 1H), 7.21(d,J=2Hz, 1H), 7.83(d, J=3Hz, 1H), 7.84(d, J=3Hz, 1H), 7.95(s, 1H), 8.02(s,1H) 1353

¹H-NMR(CDCl₃)δppm: 3.45(s, 3H), 5.20(s, 2H), 5.39(s, 2H), 6.88(dd, J=2,8Hz, 1H), 7.00(d, J=8Hz, 1H), 7.12(d, J=2Hz, 1H), 7.83(d, J=3Hz, 1H),7.85(d, J=3Hz, 1H), 8.13(s, 1H), 8.79(s, 1H) 1354

¹H-NMR(CDCl₃)δppm: 3.40(s, 3H), 5.15(s, 2H), 5.61(s, 2H), 6.75(dd, J=2,8Hz, 1H), 6.96(d, J=2Hz, 1H), 7.01(d, J=8Hz, 1H), 7.83(d, J=3Hz, 1H),7.86(d, J=3Hz, 1H), 8.26(s, 1H), 8.91(s, 1H) 1355

¹H-NMR(CDCl₃)δppm: 3.46(s, 3H), 5.21(s, 2H), 5.42(s, 2H), 6.90(dd, J=2,8Hz, 1H), 7.00(d, J=8Hz, 1H), 7.15(d, J=2Hz, 1H), 7.83(d, J=3Hz, 1H),7.86(d, J=3Hz, 1H), 8.29(s, 1H), 9.01(s, 1H) 1356

¹H-NMR(DMSO-d₆)δppm: 3.28(s, 3H), 5.13(s, 2H), 5.32(s, 2H), 6.93(dd,J=2, 8Hz, 1H), 7.06(d, J=2Hz, 1H), 7.10(d, J=8Hz, 1H), 7.27(s, 2H),7.90-7.94(m, 1H), 7.95-7.98(m, 1H), 8.16(s, 1H), 8.24(s, 1H) 1357

¹H-NMR(CDCl₃)δppm: 3.34(s, 3H), 3.45(s, 3H), 3.92(s, 3H), 5.17(s, 2H),5.43(s, 2H), 6.91-6.99(m, 3H), 7.82(m, 2H), 8.00(s, 1H) 1358

¹H-NMR(CDCl₃)δppm: 2.47(s, 3H), 3.38(s, 3H), 3.52(br.s, 6H), 5.12(s,2H), 5.26(s, 2H), 6.72(dd, J=2, 8Hz, 1H), 6.93(d, J=8Hz, 1H), 6.96(d,J=2Hz, 1H), 7.82(d, J=3Hz, 1H), 7.84(d, J=3Hz, 1H), 8.32(s, 1H) 1359

¹H-NMR(DMSO-d₆)δppm: 2.35(s, 3H), 2.48(s, 3H), 3.24(s, 3H), 5.09(s, 2H),5.24(s, 2H), 6.79(d, J=8Hz, 1H), 6.90(s, 1H), 7.09(d, J=8Hz, 1H),7.92(d, J=3Hz, 1H), 7.95(d, J=3Hz, 1H), 12.14(s, 1H) 1360

¹H-NMR(CDCl₃)δppm: 3.24(s, 6H), 3.47(s, 3H), 4.99(s, 2H), 5.20(s, 2H),6.93(d, J=8Hz, 1H), 7.00(dd, J=2, 8Hz, 1H), 7.27(d, J=2Hz, 1H), 7.82(m,2H), 8.24(s, 1H), 10.36(s, 1H) 1361

¹H-NMR(DMSO-d₆)δppm: 3.20(s, 3H), 3.31(s, 3H)m 3.39(s, 3H), 5.14(s, 2H),5.40(s, 2H), 6.95(dd, J=1.4, 8.2Hz, 1H), 7.08(d, J=1.4Hz, 1H), 7.09(d,J=8.2Hz, 1H), 7.91(d, J=2.8Hz, 1H), 7.95(d, J=2.8Hz, 1H), 8.26(s, 1H)1362

¹H-NMR(CDCl₃)δppm: 3.39(s, 3H), 5.13(s, 2H), 5.32(s, 2H), 6.82(dd, J=2,8Hz, 1H), 6.93(d, J=8Hz, 1H), 7.06(d, J=2Hz, 1H), 7.73(d, J=3Hz, 1H),7.79(d, J=3Hz, 1H), 8.08(s, 1H), 8.68(s, 1H) 1363

¹H-NMR(CDCl₃)δppm: 3.32(s, 3H), 5.08(s, 2H), 5.59(s, 2H), 6.67(dd, J=2,8Hz, 1H), 6.87(d, J=2Hz, 1H), 6.95(d, J=8Hz, 1H), 7.77(d, J=3Hz, 1H),7.80(d, J=3Hz, 1H), 8.21(s, 1H), 8.80(s, 1H)

Examples

The following compounds were obtained each as yellow crystals bytreating the methoxymethyl compounds in the above table by the samemethod as the one of Example 434.

Ex. Structural formula MS M.p. NMR 1364

ESI(+) 334.1 (MH⁺) 264- 265° C. ¹H-NMR(DMSO-d₆)δppm: 5.34(s, 2H),6.59(s, 1H), 6.74(d, J=8.6Hz, 1H), 6.88(d, J=8.6Hz, 1H), 7.61(s, 2H),8.69(s, 1H), 8.93(s, 1H), 9.18(s, 1H), 9.44(br.s, 1H) 1365

ESI(+) 334.2 (MH⁺) 277- 280° C. ¹H-NMR(DMSO-d₆)δppm: 5.46(s, 2H),6.60(s, 1H), 6.80(d, J=8.0Hz, 1H), 6.91(d, J=8.0Hz, 1H), 7.61(s, 2H),8.81(s, 1H), 8.97(s, 1H), 9.07(s, 1H), 9.43(br.s, 1H) 1366

ESI(+) 349 (MH⁺⁾ 290° C.< ¹H-NMR(DMSO-d₆)δppm: 5.20(s, 2H), 6.60(d,J=2Hz, 1H), 6.72(dd, J=2, 8Hz, 1H), 6.89(d, J=8Hz, 1H), 7.27(s, 2H),7.63(s, 2H), 8.14(s, 1H), 8.20(s, 1H), 9.50(s, 1H)

Examples

The following compounds were obtained each as yellow crystals bytreating the methoxymethyl compounds in the above table by the samemethod as the one of Example 9.

Ex. Structural formula MS M.p. NMR 1367

ESI (+) 348 (MH⁺) 276- 278° C. ¹H-NMR(DMSO-d₆) δ ppm: 2,57(s, 3H),5.57(s, 2H), 6.32(s, 1H), 6.57(d, J=8Hz, 1H), 6.90(d, J=8Hz, 1H),7.60(s, 2H), 8.71(s, 1H), 8.79(s, 1H), 9.38(s, 1H) 1368

¹H-NMR(DMSO-d₆) δ ppm: 2.71(s, 3H), 5.31(s, 2H), 6.57(s, 1H), 6.72(d,J=8Hz, 1H), 7.61(s, 2H), 8.59(s, 1H), 8.76(s, 1H), 9.43(s, 1H) 1369

FAB (+) 377 (MH⁺) 229- 233° C. ¹H-NMR(DMSO-d₆) δ ppm: 3.43(s, 6H),5.20(s, 2H), 6.56(d, J=1Hz, 1H), 6.67(dd, J=1, 8Hz, 1H), 6.86(d, J=8Hz,1H), 7.62(s, 2H), 8.19(s, 1H), 8.21(s, 1H), 9.46(s, 1H) 1370

FAB (+) 377 (MH⁺) 265- 268° C. ¹H-NMR(DMSO-d₆) δ ppm: 3.39(s, 3H),3.83(s, 3H), 5.34(s, 2H), 6.69(d, J=1Hz, 1H), 6.78(dd, J=1, 8Hz, 1H),6.87(d, J=8Hz, 1H), 7.61(s, 2H), 7.71(s, 1H), 8.52(s, 1H), 9.40(s, 1H)1371

FAB (+) 367 (M⁺) ¹H-NMR(DMSO-d₆) δ ppm: 5.36(s, 2H), 6.54(s, 1H),6.75(d, J=8Hz, 1H), 6.87(d, J=8Hz, 1H), 7.61(s, 2H), 8.78(s, 2H),9.40(s, 1H) 1372

FAB (+) 367 (M⁺) ¹H-NMR(DMSO-d₆) δ ppm: 5.57(s, 2H), 6.39(d, J=1Hz, 1H),6.65(dd, J=1, 8Hz, 1H), 6.89(d, J=8Hz, 1H), 7.60(d, J=3Hz, 1H), 7.61(d,J=3Hz, 1H), 8,83(s, 1H), 8.94(s, 1H), 9.35(s, 1H) 1373

272- 274° C. ¹H-NMR(DMSO-d₆) δ ppm: 5.42(s, 2H), 6.56(d, J=2Hz, 1H),6.78(dd, J=2, 8Hz, 1H), 6.88(d, J=8Hz, 1H), 7,62(s, 2H), 9.02(s, 1H),9.39(s, 1H), 9.40(s, 1H) 1374

FAB (+) 444 (M⁺) 231- 233° C. ¹H-NMR(CDCl₃) δ ppm: 3.37(s, 3H), 3.95(s,3H), 5.35(s, 2H), 6.44(d, J=1Hz, 1H), 6.75(dd, J=1, 8Hz, 1H), 6.78(br.s,1H), 6.83(d, J=8Hz, 1H), 7.55(d, J=3Hz, 1H), 7.67(d, J=3Hz, 1H), 7.90(s,1H) 1375

¹H-NMR(CDCl₃) δ ppm: 2.45(s, 3H), 3.54(s, 6H), 5.19(s, 2H), 6.22(d,J=1Hz, 1H), 6.42(br.s, 1H), 6.63(dd, J=1, 8Hz, 1H), 6.83(d, J=8Hz, 1H),7.54(d, J=3Hz, 1H), 7.68(d, J=3Hz, 1H), 8.33(s, 1H) 1376

206- 211° C. ¹H-NMR(DMSO-d₆) δ ppm: 2.30 and 2.31(s, total 3H), 2.34 and2.35(s, total 3H), 5.13 and 5.49(s, total 2H), 6.43 and 6.46(s, total1H), 6.59(d, J=8Hz, 1H), 6.87(d, J=8Hz, 1H), 7.61(s, 2H), 9.44 and9.46(s, total 1H), 12.13(br.s, 1H) 1377

FAB (+) 392 (M⁺) >280° C. ¹H-NMR(DMSO-d₆) δ ppm: 3.20(s, 3H), 3.35(s,3H), 4.75(s, 2H), 6.65(s, 1H), 6.72(d, J=8Hz, 1H), 6.85(d, J=8Hz, 1H),7.60(s, 2H), 8.09(s, 1H), 9.46(s, 1H), 10.95(s, 1H)

Examples

The following compounds were obtained by treating8-(6-bromopurin-9-ylmethyl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazineby the same method as the one of Example 9 and separating and purifyingeach of the two compounds thus formed.

Ex. Structural formula MS M.p. NMR 1378

FAB (+) 350 (MH⁺) >275° C. ¹H-NMR(DMSO-d₆)δppm: 5.38(s, 2H), 6.57(d,J=1Hz, 1H), 6.68(dd, J=1, 8Hz, 1H), 6.87(d, J=8Hz, 1H), 7.61(s, 2H),7.97(d, J=4Hz, 1H), 8.30(s, 1H), 9.48(s, 1H), 12.30(s, 1H) 1379

¹H-NMR(CDCl₃)δppm: 5.21(s, 2H), 6.39(d, J=1Hz, 1H), 6.60(br.s, 1H),6.74(dd, J=1, 8Hz, 1H), 6.86(d, J=8Hz, 1H), 7.55(d, J=3Hz, 1H), 7.69(d,J=3Hz, 1H), 7.90(s, 1H), 8.56(s, 1H)

Examples

The following compounds were obtained by treating8-(6-bromopurin-9-ylmethyl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazineby the same method as the one of Example 9 and separating and purifyingeach of the two compounds thus formed.

Ex. Structural formula MS M.p. NMR 1380

FAB (+) 349 (M⁺) >275° C. ¹H-NMR(DMSO-d₆)δppm: 5.20(s, 2H), 6.53(d,J=1Hz, 1H), 6.69(dd, J=1, 8Hz, 1H), 6.87(d, J=8Hz, 1H), 7.62(s, 2H),8.02(d, J=4Hz, 1H), 8.14(s, 1H), 9.45(s, 1H), 12.31(s, 1H) 1381

¹H-NMR(CDCl₃)δppm: 5.22(s, 2H), 6.36(d, J=1Hz, 1H), 6.43(br.s, 1H),6.70(dd, J=1, 8Hz, 1H), 6.82(d, J=8Hz, 1H), 7.50(d, J=3Hz, 1H), 7.64(d,J=3Hz, 1H), 8.06(s, 1H), 8.67(s, 1H)

Example 13829-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione

The title compound was obtained by treating9-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dioneby the same method as the one of Example 9.

¹H-NMR(DMSO-d₆) δ ppm: 3.19(s, 3H), 3.43(s, 3H), 5.32(s, 2H), 6.59(d,J=2 Hz, 1H), 6.68(d, J=8 Hz, 1H), 6.87(dd, J=2, 8 Hz, 1H), 7.62(m, 2H),8.20(s, 1H), 9.47(s, 1H)

m.p.: 264-266° C.

Example 13838-(2,6-Dichloropurin-9-ylmethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine

The title compound was obtained by reacting8-chloromethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazinewith 2,6-dichloropurine by the same method as the one of Example 1348followed by the same treatment as the one of Example 434.

¹H-NMR(CDCl₃) δ ppm: 5.44(s, 2H), 6.20(d, J=1 Hz, 1H), 6.55(dd, J=1, 8Hz, 1H), 6.59(br.s, 1H), 6.83(d. J=8 Hz, 1H), 7.49(d, =3 Hz, 1H),7.65(d, J=3 Hz, 1H), 8.19(s, 1H)

MS: FAB(+)401(M⁺)

Examples

The following compounds were obtained by reacting8-chloromethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazinewith 8-methylpurine by the same method as the one of Example 1348 tothereby give8-(8-methylpurin-9(7)-ylmethyl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazineand then treating this product by the same method as the one of Example9.

Ex. Structural formula MS M.p. NMR 1384

ESI(+) 348 (MH⁺) 191- 193° C. ¹H-NMR(DMSO-d₆)δppm: 248(s, 3H), 5.31(s,2H), 6.48(s, 1H), 6.68(d, J=8Hz, 1H), 6.88(d, J=8Hz, 1H), 7.60(s, 2H),8.86(d, J=1Hz, 1H), 9.01(d, J=1Hz, 1H), 9.39(br.s, 1H) 1385

ESI(+) 348 (MH⁺) >275° C. ¹H-NMR(DMSO-d₆)δppm: 2.59(s, 3H), 5.42(s, 2H),6.47(d, J=2Hz, 1H), 6.70(dd, J=2, 8Hz, 1H), 6.89(d, J=8Hz, 1H), 7.59(s,2H), 8.89(s, 1H), 9.00(s, 1H), 9.37(s, 1H

Example 13868-[6-(Morpholin-4-yl)purin-9-ylmethyl]-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine

0.222 g of the title compound was obtained as a yellow solid by treating0.21 g of8-(6-chloropurin-9-ylmethyl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazinewith 0.5 ml of morpholine in dichloromethane by the same method as theone of Example 1244.

¹H-NMR(CDCl₃) δ ppm: 3.44(s, 3H), 3.83(t, J=5 Hz, 4H), 4.26-4.35(br.s,4H), 5.18(s, 2H), 5.29(s, 2H), 6.83(d, J=8 Hz, 1H), 6.97(d, J=8 Hz, 1H),7.07(s, 1H), 7.62(s, 1H), 7.81-7.83(m, 2H), 8.38(s, 1H)

Examples

The following compounds were obtained by treating8-(6-chloropurin-9-ylmethyl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazinewith various amines by the same method as the one of Example 1244.

Ex. Structural formula NMR 1387

¹H-NMR (CDCl₃) δ ppm: 1.65-1.77(m, 6H), 3.43(s, 3H), 4.24(br.s, 4H),5.17(s, 2H), 5.28(s, 2H), 6.84(dd, J=2, 8Hz, 1H), 6.94(d, J=8Hz, 1H),7.08(d, J=2Hz, 1H), 7.71(s, 1H), 7.83(d, J=3Hz, 1H), 7.84(d, J=3Hz, 1H),8.36(s, 1H) 1388

¹H-NMR (CDCl₃) δ ppm: 1.28(d, J=7Hz, 6H), 2.75-2.87(br.s, 2H), 3.44(s,3H), 3.72(br.s, 2H), 5,18(s, 2H), 5.29(s, 2H), 5.30(br.s, 2H), 6.83(dd,J=2, 8Hz, 1H), 6.96(d, J=8Hz, 1H), 7.09(d, J=2Hz, 1H), 7.73(s, 1H),7.83(d, J=3Hz, 1H), 7.84(d, J=3Hz, 1H), 8.37(s, 1H) 1389

¹H-NMR (CDCl₃) δ ppm: 2.35(s,3H), 2.55(m, 4H), 3.43(s, 3H), 4.33(br.s,4H), 5.18(s, 2H), 5.29(s, 2H), 6.83(dd, J=2, 8Hz, 1H), 6.94(d, J=8Hz,1H), 7.08(d, J=2Hz, 1H), 7.63(s, 1H), 7.83(d, J=3Hz, 1H), 7.84(d, J=3Hz,1H), 8.37(s, 1H) 1390

¹H-NMR (CDCl₃) δ ppm: 1.62(m, 2H), 2.03(m, 2H), 3.43(s, 3H), 3.72(br.s,2H), 4.02(br.s, 2H), 4.91(br.m, 1H), 5.17(s, 2H), 5.28(s, 2H), 6.84(dd,J=2, 8Hz, 1H), 6.96(d, J=8Hz, 1H), 7.09(d, J=2Hz, 1H), 7.73(s, 1H),7.83(d, J=3Hz, 1H), 7.84(d, J=3Hz, 1H), 8.37(s, 1H) 1391

¹H-NMR (CDCl₃) δ ppm: 1.52(m, 2H), 1.91(m, 2H), 2.59(m, 1H), 3.2(m, 4H),3.24(s, 3H), 5.11(s, 2H), 5.22(s, 2H), 6.91(dd, J=2, 8Hz, 1H), 7.02(d,J=2Hz, 1H), 7.07(d, J=8Hz, 1H), 7.91(d, J=3Hz, 1H), 7.94(d, J=3Hz, 1H),8.23(s, 1H), 8.28(s, 1H) 1392

¹H-NMR (CDCl₃) δ ppm: 0.97 and 0.99(d, J=7Hz, total 6H), 1.50-1.92(m,4H), 2.48(br.s, 2H), 3.43(s, 3H), 5.17(s, 2H), 5.28(s, 2H), 5.32(br.s,2H), 6.83(dd, J=2, 8Hz, 1H), 6.94(d, J=8Hz, 1H), 7.08(d, J=2Hz, 1H),7.71(s, 1H), 7.83(d, J=3Hz, 1H), 7.84(d, J=3Hz, 1H), 8.36(s, 1H) 1393

¹H-NMR (CDCl₃) δ ppm: 1.32(dq, J=4, 11Hz, 2H), 1.81(br.d, J=11Hz, 2H),1.85-1.94(m, 1H), 2.56(d, J=8Hz, 2H), 3.02(m, 2H), 3.44(s, 3H), 5.18(s,2H), 5.28(s, 2H), 5.43(m, 2H), 6.83(dd, J=2, 8Hz, 1H), 6.96(d, J=8Hz,1H), 7.08(d, J=2Hz, 1H), 7.13—7.31(m, 5H), 7.71(s, 1H), 7.83(d, J=3Hz,1H), 7.84(d, J=3Hz, 1H), 8.35(s, 1H) 1394

¹H-NMR (CDCl₃) δ ppm: 2.58(t, J=5Hz, 4H), 3.43(s, 3H), 3.57(s, 2H),4.32(br.s, 4H), 5.17(s, 2H), 5.28(s, 2H), 6.83(dd, J=2, 8Hz, 1H),6.94(d, J=8Hz, 1H), 7.07(d, J=2Hz, 1H), 7.26-7.35(m, 5H), 7.71(s, 1H),7.83(d, J=3Hz, 1H), 7.84(d, J=3Hz, 1H), 8.36(s, 1H) 1395

¹H-NMR (CDCl₃) δ ppm: 1.79(dq, J=4, 11Hz, 2H), 2.03(br.d, J=11Hz, 2H),2.88(tt, J=1, 11Hz, 1H), 3.16(br.t, J=11Hz, 2H),3.45(s, 3H), 5.19(s,2H), 5.30(s, 2H), 5.65(br.s, 2H), 6.85(dd, J=2, 8Hz, 1H), 6.97(d, J=8Hz,1H), 7.10(d, J=2Hz, 1H), 7.21-7.32(m, 5H), 7.74(s, 1H), 7.83(d, J=3Hz,1H), 7.84(d, J=3Hz, 1H), 8.39(s, 1H) 1396

¹H-NMR (CDCl₃) δ ppm: 2.32(t, J=6Hz, 2H), 2.45(m, 4H), 2.66(t, J=6Hz,2H), 3.26(s, 3H), 4.39(m, 4H), 5.11(s, 2H), 5.30(s, 2H), 6.90(dd, J=2,8Hz, 1H), 7.03(d, J=2Hz, 1H), 7.07(d, J=8Hz, 1H), 7.91(d, J=3Hz, 1H),7.94(d, J=3Hz, 1H), 8.23(s, 1H), 8.28(s, 1H) 1397

¹H-NMR (CDCl₃) δ ppm: 3.21(br.s, 3H), 3.43(s, 3H), 5.18(s, 2H), 5.29(s,2H), 6.84(d, J=2, 8Hz, 1H), 6.97(d, J=8Hz, 1H), 7.08(s, 1H), 7.62(s,1H), 7.82-7.84(m, 2H), 8.44(s, 1H)

Examples

The following compounds were obtained by treating the compounds obtainedin the above table by the same method as the one of Example 9.

Ex. Structural formula MS M.p. NMR 1398

FAB (+) 419 (MH+) ¹H-NMR (CDCl₃) δ ppm: 3.84(t, J=5Hz, 4H), 4.30(br.s,4H), 5.20(s, 2H), 6.37(d, J=1, 1H), 6.40(br.s, 1H), 6.73(dd, J=1, 8Hz,1H), 6.85(d, J=8Hz, 1H), 7.55(d, J=3Hz, 1H), 7.69(d, J=3Hz, 1H), 7.72(s,1H), 8.38(s, 1H) 1399

FAB (+) 417 (MH+) 228- 229° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.56(br.s, 4H),1.65(br.s, 2H), 4.17(br.s, 4H), 5.20(s, 2H), 6.58(d, J=1Hz, 1H),6.70(dd, J=1, 8Hz, 1H), 6.87(d, J=8Hz, 1H), 7.61(s, 2H), 8.19(s, 1H),8.21(s, 1H), 9.45(s, 1H) 1400

FAB (+) 447 (MH+) 227- 229° C. ¹H-NMR (CDCl₃) δ ppm: 1.29(d, J=7Hz, 6H),2.80(m, 2H), 3.74(m, 2H), 5.20(s, 2H), 5.30(br.s, 2H), 6.36(d, J=8Hz,1H), 6.39(s, 1H), 6.73(dd, J=1, 8Hz, 1H), 6.85(d, J=8Hz, 1H), 7.55(d,J=3Hz, 1H), 7.69(d, J=3Hz, 1H), 7.72(s, 1H), 8.36(s, 1H) 1401

FAB (+) 432 (MH⁺) 197- 202° C. ¹H-NMR (DNSO-d₆) δ ppm: 2.52(s, 3H),2.80(br.s, 4H), 4.35(br.s, 4H), 5.23(s, 2H), 6.64(d, J=1Hz, 1H), 6.67(d,J=1, 8Hz, 1H), 6.87(d, J=8Hz, 1H), 7.62(s, 2H), 8.33(s, 1H), 8.37(s,1H), 9.49(s, 1H) 1402

¹H-NMR (CDCl₃) δ ppm: 1.65(m, 2H), 2.05(m, 2H), 3.75(m,2H), 4.05(m, 2H),4.85(m, 1H), 5.20(s, 2H), 6.38(d, J=1Hz, 1H), 6.47(s, 1H), 6.73(dd, J=1,8Hz, 1H), 6.85(d, J=8Hz, 1H), 7.55(d, J=3Hz, 1H), 7.67(d, J=3Hz, 1H),7.71(s, 1H), 8.36(s, 1H) 1403

FAB (+) 461 (MH⁺) 238- 240° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.53(t, J=10Hz,2H), 1.93(d, J=10Hz, 2H), 2.60(m, 1H), 3.2(br.s, 4H), 5.20(s, 2H),6.57(d, J=1Hz, 1H), 6.70(dd, J=1, 8Hz, 1H), 6.86(d, J=8Hz, 1H), 7.62(s,2H), 8.22(s, 1H), 8.25(s, 1H), 9.45(s, 1H) 1404

FAB (+) 445 (MH⁺) 237- 238° C. ¹H-NMR (CDCl₃) δ ppm: 0.87 and 0.91(d,J=7Hz, total 6H), 1.5 and 1.6(m, total 2H), 1.8 and 1.9(m, total 2H),3.2(m, 4H), 5.20(s, 2H), 6.58 and 6.61(d, J=1Hz, total 1H), 6.70(dd,J=1, 8Hz, 1H), 6.85(d, J=8Hz, 1H), 7.62(s, 2H), # 8.17 and 8.20(s, total1H), 8.20 and 8.22(s, total 1H), 9.47 and 9.48(s, total 1H) 1405

FAB (+) 507 (MH⁺) 186- 188° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.2(m, 4H),1.65(m, 1H), 2.50(d, J=7Hz, 2H), 3.2(br.s, 4H), 5.20(s, 2H), 6.59(d,J=1Hz, 1H), 6.70(dd, J=1, 8Hz, 1H), 6.87(d, J=8Hz, 1H), 7.15-7.18(m,3H), 7.27(dd, J=7, 8Hz, 2H), # 7.62(s, 2H), 8.19(s, 1H), 8.21(s, 1H),9.47(s, 1H) 1406

FAB (+) 508 (MH⁺) 213- 214° C. ¹H-NMR (DMSO-d₆) δ ppm: 2.45(br.t, J=7Hz,4H), 3.50(s, 2H), 4.20(br.s, 4H), 5.21(s, 2H), 6.56(d, J=1Hz, 1H),6.69(dd, J=1, 7Hz, 1H), 6.86(d, J=7Hz, 1H), 7.25(m, 1H),7.30-7.36(m,4H), 7.61(s, 2H), 8.21(s, 1H), 8.23(s, 1H), 9.45(s, 1H) 1407

FAB (+) 493 (MH⁺) 239- 241° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.63(dq, J=4,12Hz, 2H), 1.99(br.d, J=12Hz, 2H), 2.89(tt, J=2, 12Hz, 1H), 3.1(br.s,2H), 3.3(br.s, 2H), 5.22(s, 2H), 6.60(d, J=1Hz, 1H), 6.72(dd, J=1, 8Hz,1H), 6.87(d, J=8Hz, 1H), # 7.16(tt, J=1, 7Hz, 1H), 7.22-7.29(m, 4H),7.62(s, 2H), 8.23(s, 1H), 8.25(s, 1H), 9.47(s, 1H) 1408

FAB (+) 461 (MH⁺) 226- 229° C. ¹H-NMR (DMSO-d₆) δ ppm: 2.37(t, J=7Hz,2H), 2.49(br.s, 4H), 2.72(t, J=7Hz, 2H), 4.2(br.s, 4H), 5.21(s, 2H),6.60(d, J=1Hz, 1H), 6.69(dd, J=1, 8Hz, 1H), 6.87(d, J=8Hz, 1H), 7.62(s,2H), 7.63(br.s, 2H), 8.23(s, 1H), 8.26(s, 1H), 9.47(s, 1H) 1409

FAB (+) 363 (MH⁺) 279- 281° C. ¹H-NMR (DMSO-d₆) δ ppm: 2.95(br.s, 3H),5.20(s, 2H), 6.57(d, J=1Hz, 1H), 6.79(dd, J=1, 8Hz, 1H), 6.86(d, J=8Hz,1H), 7.61(s, 2H), 7.63(br.s, 1H), 8.17(s, 1H), 8.21(br.s, 1H), 9.47(s,1H)

Examples

The following compounds were obtained by reacting8-(6-chloropurin-7-ylmethyl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazinewith various amines by the same method as the one of Example 1244.

Ex. Structural formula NMR 1410

¹H-NMR (CDCl₃) δ ppm: 3.39(s, 3H), 3.40(t, J=5Hz, 4H), 3.85(t, J=5Hz,4H), 5.13(s, 2H), 5.41(s, 2H), 6.69(dd, J=2, 8Hz, 1H), 6.82(d, J=2Hz,1H), 6.97(d, J=8Hz, 1H), 7.82(d, J=3Hz, 1H), 7.85(d, J=3Hz, 1H), 8.09(s,1H), 8.75(s, 1H) 1411

¹H-NMR (CDCl₃) δ ppm: 2.98(d, J=5Hz, 3H), 3.34(s, 3H), 4.61(q, J=5Hz,1H), 5.12(s, 2H), 5.40(s, 2H), 6.72(dd, J=2, 8Hz, 1H), 6.83(d, J=2Hz,1H), 7.05(d, J=8Hz, 1H), 7.85(d, J=3Hz, 1H), 7.88(d, J=3Hz, 1H), 7.97(s,1H), 8.56(s, 1H)

Examples

The following compounds were obtained by treating the compounds obtainedin the above table by the same method as the one of Example 9.

Ex. Structural formula MS M.p. NMR 1412

FAB (+) 419 (MH⁺) 269- 273° C. ¹H-NMR (CDCl₃) δ ppm: 3.40(t, J=4Hz, 4H),3.82(t, J=4Hz, 4H), 5.35(s, 2H), 6.27(d, J=1Hz, 1H), 6.62(dd, J=1, 8Hz,1H), 6.86(d, J=8Hz, 1H), 7.23(s, 1H), 7.56(d, J=3Hz, 1H), 7.68(d, J=3Hz,1H), 8.01(s, 1H), 8.71(s, 1H) 1413

FAB (+) 363 (MH⁺) ¹H-NMR (DMSO-d₆) δ ppm: 2.89(d, J=4Hz, 3H), 5.54(s,2H), 6.38(s, 1H), 6.55(d, J=8Hz, 1H), 6.72(q, J=4Hz, 1H), 6.86(d, J=8Hz,1H), 7.60(s, 2H), 8.28(s, 1H), 8.29(s, 1H), 9.50(s, 1H)

Example 14148-(6-Dimethylamino-2-chloropurin-9-yl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine

1.1 g of the title compound was obtained as a yellow solid by reacting0.81 g of8-chloromethyl-10-methoxymethyl-10H-pyrazino2,3-b][1,4]benzothiazinewith 6-dimethylamino-2-chloropurine by the same method as the one ofExample 1348.

¹H-NMR(CDCl₃) δ ppm: 3.22-3.35(br.s, 3H), 3.48(s, 3H), 3.71(br.s, 3H),5.20(s, 2H), 5.23(s, 2H), 6.83(dd, J=2, 8 Hz, 1H), 6.97(d, J=8 Hz, 1H),7.11(d, J=2 Hz, 1H), 7.65(s, 1H), 7.83(d, J=3 Hz, 1H), 7.84(d, J=3 Hz,1H)

Example 14158-[2,6-Bis(dimethylamino)purin-9-ylmethyl]-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine

To a solution of 0.27 g of8-(6-dimethylamino-2-chloropurin-9-yl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazinein tetrahydrofuran (10 ml) was added a 50% solution of dimethylamine inmethanol. Then the resulting mixture was heated to 110° C. for 50 hoursin a sealed tube. After distilling off the solvent under reducedpressure, the residue was purified by silica gel column chromatography(eluted with dichloromethane/methanol) to thereby give 0.23 g of thetitle compound as a yellow solid.

¹H-NMR(CDCl₃) δ ppm: 3.16(s, 6H), 3.42(s, 3H), 3.46(br.s, 6H), 5.14(s,2H), 5.17(s, 2H), 6.87(dd, J=2, 8 Hz, 1H), 6.94(d, J=8 Hz, 1H), 7.06(d,J=2 Hz, 1H), 7.42(s, 1H), 7.82(d, J=3 Hz, 1H), 7.83(d, J=3 Hz, 1H)

Example 14168-[2,6-Bis(dimethylamino)purin-9-ylmethyl]-10H-pyrazino[2,3-b[]1,4]benzothiazine

The title compound was obtained by treating8-[2,6-bis(dimethylamino)purin-9-ylmethyl]-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazineby the same method as the one of Example 9.

¹H-NMR(DMSO-d₆) δ ppm: 3.07(s, 6H), 3.60(br.s, 6H), 5.03(s, 2H), 6.62(d,J=1 Hz, 1H), 6.71(dd, J=1, 8 Hz, 1H), 6.85(d, J=8 Hz, 1H), 7.61(s, 2H),7.77(s, 1H), 9.50(s, 1H)

MS: FAB(+)419(M⁺)

m.p.: 239-240° C.

Example 14178-[6-(Trimethylsilyl)ethynylpurin-9-ylmethyl]-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine

To a solution of 2.05 g of8-(6-bromopurin-9-ylmethyl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazinein N,N-dimethylformamide (20 ml) were added in a nitrogen atmosphere0.32 g of bis(triphenylphosphine) palladium (II) chloride, 0.10 g ofcuprous iodide, 1.23 ml of (tirmethylsilyl)acetylene and 0.97 ml oftriethylamine and the resulting mixture was stirred for 16 hours. Afterfurther adding bis(triphenylphosphine) palladium (II) chloride, cuprousiodide, (tirmethylsilyl)acetylene and triethylamine each in the sameamount as the one defined above, the resulting mixture was stirred atroom temperature for 24 hours and heated to 55° C. for 6 hours. Then thereaction mixture was distributed into ethyl acetate and water andfiltered through celite. The organic layer was washed with aqueousammonia several times, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. Then the residue was purified bysilica gel column chromatography (eluted with n-hexane/ethyl acetate) tothereby give 1.22 g of the title compound as a yellow solid.

¹H-NMR(CDCl₃) δ ppm: 0.33(s, 9H), 3.44(s, 3H), 5.17(s, 2H), 5.45(s, 2H),6.84(dd, J=2, 8 Hz, 1H), 6.98(d, J=8 Hz, 1H), 7.10(d, J=2 Hz, 1H),7.83(d, J=3 Hz, 1H), 7.85(d, J=3 Hz, 1H), 8.12(s, 1H), 8.95(s, 1H)

Example 14188-(6-Ethynylpurin-9-ylmethyl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine

To a solution of 0.194 g of8-[6-(tirmehtylsilyl)-ethynylpurin-9-ylmethyl]-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazinein tetrahydrofuran (15 ml) was added in a nitrogen atmosphere 0.8 ml ofa 1 M solution of tetra-n-butylammonium fluoride in tetrahydrofuran andthe resulting mixture was stirred for 16 hours. After adding ethylacetate and water, the organic layer was dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue was thenpurified by silica gel column chromatography (eluted with n-hexane/ethylacetate) to thereby give 0.076 g of the title compound as a yellowsolid.

¹H-NMR(CDCl₃) δ ppm: 3.44(s, 3H), 3.72(s, 1H), 5.19(s, 2H), 5.38(s, 2H),6.88(dd, J=2, 8 Hz, 1H), 6.99(d, J=8 Hz, 1H), 7.12(d, J=2 Hz, 1H),7.83(d, J=3 Hz, 1H), 7.85(d, J=3 Hz, 1H), 8.14(s, 1H), 8.99(s, 1H)

Example 14198-(6-Ethylpurin-9-ylmethyl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine

0.070 g of the title compound was obtained as a yellow solid by treating0.076 g of8-(6-ethynylpurin-9-ylmethyl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazineby the same method as the one of Example 20.

¹H-NMR(CDCl₃) δ ppm: 1.44(t, J=7 Hz, 3H), 3.23(q, J=7 Hz, 2H), 3.43(s,3H), 5.19(s, 2H), 5.37(s, 2H), 6.88(d, J=8 Hz, 1H), 6.97(d, J=8 Hz, 1H),7.12(s, 1H), 7.83(m, 2H), 8.09(s, 1H), 8.94(s, 1H)

Example 14203-[9-(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)purin-6-yl]-2-propyn-1-ol

The title compound was obtained by reacting8-(6-bromopurin-9-ylmethyl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazinewith propargyl alcohol by the same method as the one of Example 1417.

¹H-NMR(CDCl₃) δ ppm: 3.44(s, 3H), 4.63(s, 2H), 5.19(s, 2H), 5.38(s, 2H),6.86(dd, J=2, 8 Hz, 1H), 6.98(d, J=8 Hz, 1H), 7.12(d, J=2 Hz, 1H),7.84(m, 2H), 8.14(s, 1H), 8.97(s, 1H)

Example 14213-[9-(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)purin-6-yl]-1-propanol

0.028 g of the title compound was obtained as yellow crystals bytreating 0.088 g of3-[9-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)purin-6-yl]-2-propyn-1-olby the same method as the one of Example 20.

¹H-NMR(CDCl₃) δ ppm: 2.11(quint, J=7 Hz, 2H), 3.38(d, J=7 Hz, 2H),3.44(s, 3H), 3.65(t, J=7 Hz, 2H), 5.19(s, 2H), 5.37(s, 2H), 6.89(dd,J=2, 8 Hz, 1H), 6.98(d, J=8 Hz, 1H), 7.03(d, J=2 Hz, 1H), 7.83(d, J=3Hz, 1H), 7.84(d, J=3 Hz, 1H), 8.05(s, 1H), 8.91(s, 1H)

Examples

The following compounds were obtained by treating8-(6-ethylpurin-9-ylmethyl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine,3-[9-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)purin-6-yl]-1-propanoland3-[9-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)purin-6-yl]-2-propyn-1-olby the same method as the one of Example 9.

Ex. Structural formula MS M.p. NMR 1422

FAB (+) 361 (M⁺) 215- 217° C. ¹H-NMR (CDCl₃) δ ppm: 1.45(t, J=7Hz, 3H),3.22(q, J=7Hz, 2H), 5.26(s, 2H), 6.43(d, J=1Hz, 1H), 6.68(br.s, IH),6.77(dd, J=1, 8Hz, 1H), 6.87(d, J=8Hz, 1H), 7.54(d, J=3Hz, 1H), 7.69(d,J=3Hz, 1H), 8.01(s, 1H), 8.90(s, 1H) 1423

FAB (+) 392 (MH⁺) 174- 177° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.95(quint,J=7Hz, 2H), 3.10(t, J=7Hz, 2H), 3.47(q, J=7Hz, 2H), 4.55(t, J=7Hz, 1H),5.21(s, 2H), 6.60(d, J=1Hz, 1H), 6.75(dd, J=1, 9Hz, 1H), 6.87(d, J=9Hz,1H), 7.61(s, 2H), 8.57(s, 1H), 8.78(s, 1H), 9.45(s, 1H) 1424

152- 154° C. (decom- pose) ¹H-NMR (DMSO-d₆) δ ppm: 4.46(d, J=6Hz, 2H),5.34(s, 2H), 5.61(t, J=6Hz, 1H), 6.54(s, 1H), 6.76(d, J=8Hz, 1H),6.88(d, J=8Hz, 1H), 7.61(s, 2H), 8.72(s, 1H), 8.87(s, 1H), 9.42(s, 1H)

Example 14258-(6-Iodopurin-9-ylmethyl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine

The title compound was obtained by treating8-chloromethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazinewith 6-iodopurine by the same method as the one of Example 1094.

¹H-NMR(CDCl₃) δ ppm: 3.46(s, 3H), 5.20(s, 2H), 5.36(s, 2H), 6.88(dd,J=2, 8 Hz, 1H), 6.99(d, J=8 Hz, 1H), 7.12(d, J=2 Hz, 1H), 7.84(d, J=3Hz, 1H), 7.86(d, J=3 Hz, 1H), 8.14(s, 1H), 8.68(s, 1H)

Example 14264-[9-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)purin-6-yl]-2-methyl-3-butyn-2-ol

8-(6-Iodopurin-9-ylmethyl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazinewas treated by the same method as the one of Example 9 to thereby give8-(6-iodopurin-9-ylmethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine. Next,this product was treated with 2-methyl-3-butyn-2-ol by the same methodas the one of Example 1417 to thereby give the title compound.

¹H-NMR(DMSO-d₆) δ ppm: 1.52(s, 6H), 5.32(s, 2H), 5.78(s, 1H), 6.51(d,J=1Hz, 1H), 6.73(dd, J=1, 8 Hz, 1H), 6.87(d, J=8 Hz, 1H), 7.60(s, 2H),8.71(s, 1H), 8.85(s, 1H), 9.40(s, 1H)

Example 14274-[[9-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)purin-6-yl]-2-hydroxymethyl-3-butyne-1,2-diol

8-(6-Iodopurin-9-ylmethyl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazinewas treated by the same method as the one of Example 9 to thereby give8-(6-iodopurin-9-ylmethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine. Next,this product was treated withbis(tert-butyldimethylsiloxymethyl)-2-propyn-1-ol by the same method asthe one of Example 1417. The compound thus obtained was further treatedwith tetrabutylammonium fluoride in accordance with the method ofExample 1386-3 to thereby give the title compound.

¹H-NMR(DMSO-d₆) δ ppm: 3.53-3.61(m, 4H), 4.94(t, J=6 Hz, 2H), 5.34(s,2H), 5.62(s, 1H), 6.51(s, 1H), 6.73(d, J=8 Hz, 1H), 6.87(d, J=8 Hz, 1H),7.61(s, 2H), 8.70(s, 1H), 8.85(s, 1H), 9.40(s, 1H)

m.p.: 79-84° C.

Example 142810-Methoxymethyl-8-(6-ethylpurin-7-ylmethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine

To a solution of 0.30 g of8-(6-chloropurin-7-ylmethyl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazinein N,N-dimethylformamide (10 ml) were added in a nitrogen atmosphere0.312 g of vinyl-tri-n-butyltin (IV) and 0.050 g ofbis(triphenylphosphine) palladium (II) chloride. After degassing, themixture was heated to 80° C. for 20 hours. Then the insoluble matterswere removed by filtering through celite. After distilling off thesolvent under reduced pressure, the residue was purified by silica gelcolumn chromatography (eluted with dichloromethane/methanol) to therebygive 0.19 g of10-methoxymethyl-8-(6-vinylpurin-7-ylmethyl)-10H-pyrazino[2,3-b][1,4]benzothiazineas a yellow solid. To a solution of 190 mg of the obtained compound inmethanol (20 ml) was added 0.018 g of palladium/carbon and hydrogenationwas effected in a hydrogengas stream for 2 hours. Thus, 0.10 g of thetitle compound was obtained as a yellow solid.

¹H-NMR(CDCl₃) δ ppm: 1.28(t, J=7 Hz, 3H), 2.97(q, J=7 Hz, 2H), 3.31(s,3H), 5.08(s, 2H), 5.50(s, 2H), 6.62(dd, J=2, 8 Hz, 1H), 6.74(d, J=2 Hz,1H), 6.99(d, J=8 Hz, 1H), 7.83(d, J=3 Hz, 1H), 7.86(d, J=3 Hz, 1H),8.20(s, 1H), 9.05(s, 1H)

Example 14298-[6-(1-Ethoxyvinyl)purin-7-ylmethyl]-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine

To a solution of 0.9 g of8-(6-chloropurin-7-ylmethyl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazinein N,N-dimethylformamide (15 ml) were added in a nitrogen atmosphere1.03 g of 1-ethoxyvinyl-tri-n-butyltin (IV) and 0.015 g ofbis(triphenylphosphine) palladium (II) chloride. After degassing, themixture was heated to 80° C. for 20 hours. Then the insoluble matterswere removed by filtering through celite. After distilling off thesolvent under reduced pressure, the residue was purified by silica gelcolumn chromatography (eluted with dichloromethane/methanol) to therebygive 0.77 g of the title compound as yellow crystals.

¹H-NMR(CDCl₃) δ ppm: 1.34(t, J=7 Hz, 3H), 3.32(s, 3H), 3.93(q, J=7 Hz,2H), 4.54(d, J=3 Hz, 1H), 4.94(d, J=3 Hz, 1H), 5.09(s, 2H), 5.54(s, 2H),6.60(dd, J=2, 8 Hz, 1H), 6.77(d, J=2 Hz, 1H), 6.94(d, J=8 Hz, 1H),7.82(d, J=3 Hz, 1H), 7.85(d, J=3 Hz, 1H), 8.23(s, 1H), 9.09(s, 1H)

Example 14308-(6-(Ethylpurin-7-ylmethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine

The title compound was obtained by treating10-methoxymethyl-8-(6-ethylpurin-7-ylmethyl)-10H-pyrazino[2,3-b][1,4]benzothiazineby the same method as the one of Example 9.

¹H-NMR(CDCl₃) δ ppm: 1.45(t, J=7 Hz, 3H), 3.24(q, J=7 Hz, 2H), 5.26(s,2H), 6.44(s, 1H), 6.62(br.s, 1H), 6.75(d, J=8 Hz, 1H), 6.87(d, J=8 Hz,1H), 7.55(s, 1H), 7.69(s, 1H), 8.02(s, 1H), 8.90(s, 1H)

MS: FAB(+)362(MH⁺)

M.P.: >275° C.

Example 14318-(6-Acetylpurin-7-ylmethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine

The title compound was obtained by treating8-[6-(1-ethoxyvinyl)purin-7-ylmethyl]-10H-pyrazino[2,3-b][1,4]benzothiazineby the same method as the one of Example 8.

¹H-NMR(DMSO-d₆) δ ppm: 2.59(s, 3H), 5.58(s, 2H), 6.25(s, 1H), 6.47(d,J=8 Hz, 1H), 6.84(d, J=8 Hz, 1H), 7.59(d, J=3 Hz, 1H), 7.60(d, J=3 Hz,1H), 8.98(s, 1H), 9.15(s, 1H), 9.34(s, 1H)

MS: FAB(+)375(M⁺)

m.p.: 266-268° C.

Example 14328-(6-Acetylpurin-7-ylmethyl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine

0.21 g of the title compound was obtained as yellow crystals by treating0.316 g of8-(6-acetylpurin-7-ylmethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine bythe same method as the one of Example 5.

¹H-NMR(CDCl₃) δ ppm: 2.71(s, 3H), 3.36(s, 3H), 5.09(s, 2H), 5.72(s.,2H), 6.62(dd, J=2, 8 Hz, 1H), 6.92(d, J=2 Hz, 1H), 6.94(d, J=8 Hz, 1H),7.81(d, J=3 Hz, 1H), 7.84(d, J=3 Hz, 1H), 8.40(s, 1H), 9.21(s, 1H)

Example 14331-[7-(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)purin-6-yl]ethanol

0.08 g of the title compound was obtained as yellow crystals by treating0.13 g of8-(6-acetylpurin-7-ylmethyl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazinewith diisobutylaluminum hydride by the same method as the one of Example6.

¹H-NMR(CDCl₃) δ ppm: 1.46(d, J=7 Hz, 3H), 1.93(br.s, 1H), 3.32(s, 3H),5.07-5.14(m, 3H), 5.50(d, J=15 Hz, 1H), 5.64(d, J=15 Hz, 1H), 6.62(dd,J=2, 8 Hz, 1H), 6.77(d, J=2 Hz, 1H), 6.97(d, J=8 Hz, 1H), 7.81(d, J=3Hz, 1H), 7.84(d, J=3 Hz, 1H), 8.21(s, 1H), 9.03(s, 1H)

Example 14342-[7-(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)purin-6-yl]-2-propanol

0.148 g of the title compound was obtained as yellow crystals bytreating 0.21 g of8-(6-acetylpurin-7-ylmethyl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazinewith methylmagnesium bromide by the same method as the one of ProductionExample 86.

¹H-NMR(CDCl₃) δ ppm: 1.66(s, 6H), 2.64(br.s, 1H), 3.30(s, 3H), 5.07(s,2H), 5.90(s, 2H), 6.60(d, J=8 Hz, 1H), 6.65(s, 1H), 6.96(d, J=8 Hz, 1H),7.81-7.84(m, 2H), 8.18(s, 1H), 9.01(s, 1H)

Examples

The following compounds were obtained by treating1-[7-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)purin-6-yl]ethanoland2-[7-(10-methoxymethyl-10H-pyrazino[2,3-b](1,4]benzothiazin-8-ylmethyl)purin-6-yl]-2-propanolby the same method as the one of Example 9.

Ex. Structural formula MS M.p. NMR 1435

FAB (+) 377 (M⁺) 205- 208° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.37(d, J=6Hz,3H), 4.89(quint, J=6Hz, 1H), 5.70(s, 2H), 5.78(d, J=6Hz, 1H), 6.30(d,J=1Hz, 1H), 6.52(dd, J=1, 9Hz, 1H), 6.68(d, J=9Hz, 1H), 7.60(s, 2H),8.73(s, 1H), 8.90(s, 1H), 9.35(s, 1H) 1436

FAB (+) 391 (M⁺) 268- 271° C. ¹H-NMR (DMSO-d₆) δ ppm: 1.42(s, 6H),5.90(s, 1H), 5.96(s, 2H), 6.25(d, J=1Hz, 1H), 6.39(dd, J=1, 8Hz, 1H),6.85(d, J=8Hz, 1H), 7.61(s, 2H), 8.67(s, 1H), 8.85(s, 1H), 9.38(s, 1H)

Examples

The following compounds were obtained by reacting8-chloromethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzoxazine and8-chloromethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazinewith 2-(purin-6-yl)-2-propanol by the same method as the one of Example1094.

Ex. Structural formula NMR 1437

¹H-NMR (CDCl₃) δ ppm: 1.75(s, 6H), 3.40(s, 3H), 5.16(s, 2H), 5.36(s,2H), 6.88(dd, J=2, 8Hz, 1H), 6.96(d, J=8Hz, 1H), 7.10(d, J=2Hz, 1H),7.80(d, J=3Hz, 1H), 7.81(d, J=3Hz, 1H), 8.07(s, 1H), 8.91(s, 1H) 1438

¹H-NMR (CDCl₃) δ ppm: 1.78(s, 6H), 3.42(s, 3H), 5.26(s, 2H), 5.34(s,2H), 5.42(br.s, 1H), 6.79(d, J=8Hz, 1H), 6.81(d, J=8Hz, 1H), 6.97(s,1H), 7.44(d, J=3Hz, 1H), 7.59(d, J=3Hz, 1H), 8.08(s, 1H), 8.94(s, 1H)

Examples

The following compounds were obtained by treating the compounds in theabove table by the same method as the one of Example 9.

Ex. Structural formula MS M.p. NMR 1439

ESI (+) 392 (MH⁺) 178- 179° C. ¹H-NMR (CDCl₃) δ ppm: 1.79(s, 6H),5.31(s, 2H), 6.47(d, J=2Hz, 1H), 6.59(br.s, 1H), 6.79(dd, J=2, 8Hz, 1H),6.88(d, J=8Hz, 1H), 7.56(d, J=3Hz, 1H), 7.70(d, J=3Hz, 1H), 8.07(s, 1H),8.95(s, 1H) 1440

ESI (+) 376 (MH⁺) 143- 145° C. ¹H-NMR (CDCl₃) δ ppm: 1.79(s, 6H),5.29(s, 2H), 6.52(s, 1H), 6.76(d, J=8Hz, 1H), 6.80(d, J=8Hz, 1H),7.38(d, J=3Hz, 1H), 7.44(d, J=3Hz, 1H), 8.10(s, 1H), 8.96(s, 1H)

Examples

The following compounds were obtained by reacting8-chloromethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazinewith 2-(benzimidazol-5-yl)-2-propanol by the same method as the one ofExample 1094 followed by the same treatment as the one of Example 9.

Ex. Structural formula MS M.p. NMR 1441

¹H-NMR (DMSO-d₆) δ ppm: 1.43(s, 6H), 5.00(s, 1H), 5.32(s, 2H), 6.59(d,J=1Hz, 1H), 6.67(dd, J=1, 8Hz, 1H), 6.88(d, J=8Hz, 1H), 7.29(d, J=8Hz,1H), 7.53(s, 1H), 7.55(d, J=8Hz, 1H), 7.61(s, 2H), 8.27(s, 1H), 9.50(s,1H) 1442

¹H-NMR (DMSO-d₆) δ ppm: 1.44(s, 6H), 4.97(s, 1H), 5.29(s, 2H), 6.60(s,1H), 6.69(d, J=8Hz, 1H), 6.87(d, J=8Hz, 1H), 7.30-7.33(m, 2H), 7.60(s,2H), 7.71(s, 1H), 8.27(s, 1H), 9.46(s, 1H)

Example 14438-[6-(1-Ethoxyvinyl)purin-9-ylmethyl]-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine

1.0 g of the title compound was obtained as a yellow solid by treating1.33 g of8-(6-chloropurin-7-ylmethyl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazineby the same method as the one of Example 1429.

¹H-NMR(CDCl₃) δ ppm: 1.52(t, J=7 Hz, 3H), 3.43(s, 3H), 4.12(q, J=7 Hz,2H), 4.98(d, J=4 Hz, 1H), 5.18(s, 2H), 5.39(s, 2H), 6.15(d, J=4 Hz, 1H),6.87(d, J=8 Hz, 1H), 6.98(d, J=8 Hz, 1H), 7.12(s, 1H), 7.83(d, J=3 Hz,1H), 7.84(d, J=3 Hz, 1H), 8.09(s, 1H), 9.10(s, 1H)

Example 14448-(6-Acetylpurin-9-ylmethyl)-10-methoxymethyl-10H-pyrazino-[2,3-b][1,4]benzothiazine

0.2 g of the title compound was obtained as a yellow solid by treating0.66 g of8-[6-(1-ethoxyvinyl)purin-9-ylmethyl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazineby the same method as the one of Example 8.

H-NMR(DMSO-d₆) δ ppm: 2.79(s, 3H), 5.39(s, 2H), 6.57(d, J=1 Hz, 1H),6.75(dd, J=1, 8 Hz, 1H), 6.88(d, J=8 Hz, 1H), 7.61(s, 2H), 8.86(s, 1H),9.07(s, 1H), 9.43(s, 1H)

MS: FAB(+)376(MH⁺)

Example 14458-[6-[1-(tert-Butyldimethylsiloxy)ethyl]purin-9-ylmethyl]-10-methoxymethyl-10H-pyrazino[2,3-b](1,4]benzothiazine

1.63 g of the title compound was obtained as a yellow solid by reacting1.78 g of 8-chloromethyl-10-methoxymethyl-10H-pyrazino2,3-b][]1,4]benzothiazine with 1.26 g of6-[1-(tert-butyldimethylsiloxy)ethyl]purine by the same method as theone of Example 1094.

¹H-NMR(CDCl₃) δ ppm: 0.01(s, 3H), 0.04(s, 3H), 0.86(s, 9H), 1.64(d, J=7Hz, 3H), 3.41(s, 3H), 5.17(s, 2H), 5.34(d, J=15 Hz, 1H), 5.38(d, J=15Hz, 1H), 5.60(q, J=7 Hz, 1H), 6.89(dd, J=2, 8 Hz, 1H), 6.99(d, J=8 Hz,1H), 7.12(d, J=2 Hz, 1H), 7.82(d, J=3 Hz, 1H), 7.84(d, J=3 Hz, 1H),8.03(s, 1H), 8.98(s, 1H)

Example 14468-[6-[1-(tert-Butyldimethylsiloxy)ethyl]purin-7-ylmethyl]-10H-pyrazino[2,3-b][1,4]benzothiazine

1.35 g of the title compound was obtained by treating 1.55 g of8-[6-[1-(tert-butyldimethylsiloxy)ethyl]purin-9-ylmethyl]-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazineby the same method as the one of Example 9.

¹H-NMR(CDCl₃) δ ppm: 0.1(s, 3H), 0.04(s, 3H), 0.87(s, 9H), 1.63(d, J=7Hz, 3H), 5.26(m, 2H), 5.59(q, J=7 Hz, 1H), 6.43(br.s, 1H), 6.45(d, J=2Hz, 1H), 6.77(dd, J=2, 8 Hz, 1H), 6.86(d, J=8 Hz, 1H), 7.53(d, J=3 Hz,1H), 7.68(d, J=3 Hz, 1H), 8.01(s, 1H), 8.97(s, 1H)

Example 14471-[9-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)purin-6-yl]lethanol

0.52 g of the title compound was obtained by treating8-[6-[1-(tert-butyldimethylsiloxy)ethyl]purin-9-ylmethyl]-10H-pyrazino[2,3-b][1,4]benzothiazinewith tetrabutylammonium fluoride by the same method as the one ofExample 1418.

¹H-NMR(DMSO-d₆) δ ppm: 1.50(d, J=6 Hz, 3H), 5.29(quint, J=6 Hz, 1H),5.34(s, 2H), 5.35(d, J=6 Hz, 1H), 6.63(d, J=1 Hz, 1H), 6.75(dd, J=1, 8Hz, 1H), 6.87(d, J=8 Hz, 1H), 7.61(s, 2H), 8.64(s, 1H), 8.86(s,1H).9.46(s, 1H)

m.p.: 210-212° C.

MS: FAB(+)378(MH⁺)

Examples

The following compounds were obtained by treating8-chloromethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]-benzothiazinewith ethyl 4-(purin-6-ylthio)butanoate by the same method as the one ofExample 1094.

Ex. Structural formula NMR 1448

¹H-NMR(CDCl₃) δ ppm: 1.25(t, J=7Hz, 3H), 2.13(quint, J=7Hz, 2H), 2.51(t,J=7Hz, 2H), 3.43(s, 3H), 3.44(t, J=7Hz, 2H), 4.13(q, J=7Hz, 2H), 5.18(s,2H), 5.33(s, 2H), 6.85(dd, J=2, 8Hz, 1H), 6.98(d, J=8Hz, 1H), 7.11(d,J=2Hz, 1H), 7.83(d, J=3Hz, 1H), 7.85(d, J=3Hz, 1H), # 7.95(s, 1H),8.62(s, 1H) 1449

¹H-NMR(CDCl₃) δ ppm: 1.24(t, J=7Hz, 3H), 2.08(quint, J=7Hz, 2H), 2.44(t,J=7Hz, 2H), 3.37(s, 3H), 3.44(t, J=7Hz, 2H), 4.13(q, J=7Hz, 2H), 5.12(s,2H), 5.57(s, 2H), 6.73(dd, J=2, 8Hz, 1H), 6.87(d, J=2Hz, 1H), 7.00(d,J=8Hz, 1H), 7.83(d, J=3Hz, 1H), 7.85(d, J=3Hz, 1H), 8.07(s, # 1H),8.84(s, 1H)

Example 14504-[7-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)purin-6-ylthio]butanoicacid

To 15 ml of a solution of 0.109 g of ethyl4-[7-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)purin-6-ylthio]butanoatein dichloromethane was added in a nitrogen atmosphere 0.84 ml of a 1 Msolution of boron tribromide in dichloromethane and the resultingmixture was heated under reflux for 2 hours. Then the reaction mixturewas distributed into dichloromethane and water. The organic layer wasextracted and dried over anhydrous sodium sulfate. After distilling offthe solvent under reduced pressure, the obtained residue was purified bysilica gel column chromatography (eluted with dichloromethane/methanol)and recrystallized from diethyl ether to thereby give 40 mg of the titlecompound as yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 1.95(quint, J=7 Hz, 2H), 2.17(t, J=7 Hz, 2H),3.35(t, J=7 Hz, 2H), 5.55(s, 2H), 6.35(d, J=1 Hz, 1H), 6.58(dd, J=1, 8Hz, 1H), 6.87(d, J=8 Hz, 1H), 7.60(d, J=3 Hz, 1H), 7.61(d, J=3 Hz, 1H),8.67(s, 1H), 8.75(s, 1H), 9.41(s, 1H)

m.p.: 120-130° C.(decompose)

Example 14514-[9-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)purin-6-ylthio]butanoicacid

The title compound was obtained by treating ethyl4-[9-(10-methoxymethyl-10H-pyrazinol[2,3-b][1,4]benzothiazin-8-ylmethyl)purin-6-ylthio]butanoateby the same method as the one of Example 1450.

¹H-NMR(DMSO-d₆) δ ppm: 1.91(quint, J=8 Hz, 2H), 2.30(t, J=8 Hz, 2H),3.36(t, J=8 Hz, 2H), 5.30(s, 2H), 6.55(d, J=1 Hz, 1H), 6.72(dd, J=1, 8Hz, 1H), 6.88(d, J=8 Hz, 1H), 7.60(s, 2H), 8.53(s, 1H), 8.70(s, 1H),9.42(s, 1H)

m.p.: >180° C.(decompose)

Examples

The following compounds were obtained by reacting ethyl5-(purin-6-ylthio)pentanoate with8-chloromethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine bythe same method as the one of Example 1094.

Ex. Structural formula NMR 1452

¹H-NMR(CDCl₃) δ ppm: 1.24(t, J=7Hz, 3H), 1.82(m, 4H), 2.37(t, J=7Hz,2H), 3.40(t, J=7Hz, 2H), 3.44(s, 3H), 4.12(q, J=7Hz, 2H), 5.18(s, 2H),5.33(s, 2H), 6.84(d, J=8Hz, 1H), 6.97(d, J=8Hz, 1H), 7.09(s, 1H),7.82(d, J=3Hz, 1H), 7.84(d, J=3Hz, 1H), 7.94(s, 1H), 8.73(s, 1H) 1453

¹H-NMR(CDCl₃) δ ppm: 1.23(t, J=7Hz, 3H), 1.79(m, 4H), 2.33(m, 2H),3.35(s, 3H), 3.39(t, J=7Hz, 2H), 4.11(q, J=7Hz, 2H), 5.11(s, 2H),5.57(s, 2H), 6.72(d, J=8Hz, 1H), 6.86(s, 1H), 6.98(d, J=8Hz, 1H),7.82(m, 2H), 8.07(s, 1H), 8.83(s, 1H)

Examples

The following compounds were obtained by treating ethyl5-[9-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)purin-6-ylthio]pentanoateand ethyl5-[7-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)purin-6-ylthio]pentanoateby the same method as the one of Example 1450.

Ex. Structural formula MS M.p. NMR 1454

FAB (+) 466 (MH⁺) 243- 244° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.40-1.55(m, 4H),2.14(t, J=8Hz, 2H), 3.35(t, J=8Hz, 2H), 5.30(s, 2H), 6.55(s, 1H),6.74(d, J=8Hz, 1H), 6.87(d, J=8Hz, 1H), 7.61(s, 2H), 8.53(s, 1H),8.70(s, 1H), 9.43(s, 1H), 12.15(s, 1H) 1455

FAB (+) 488 (MNa⁺) ¹H-NMR(DMSO-d₆) δ ppm: 1.56(m, 2H), 1.63(m, 2H),2.17(t, J=7Hz, 2H), 3.40(t, J=7Hz, 2H), 5.55(s, 2H), 6.35(d, J=1Hz, 1H),6.58(dd, J=1, 8Hz, 1H), 6.87(d, J=8Hz, 1H), 7.60(d, J=2Hz, 1H), 7.61(d,J=2Hz, 1H), 8.67(s, 1H), 8.75(s, 1H), 9.42(s, 1H) 1456

FAB (+) 494 (MH⁺) 175- 178° C. ¹H-NMR(CDCl₃) δ ppm: 1.25(t, J=7Hz, 3H),1.78(m, 2H), 1.85(m, 2H), 2.38(m, 2H), 3.12(t, J=8Hz, 2H), 4.14(q,J=7Hz, 2H), 5.48(s, 2H), 6.35(s, 1H), 6.65(d, J=8Hz, 1H), 6.86(d, J=8Hz,1H), 7.12(s, 1H), 7.53(s, 1H), 7.67(s, 1H), # 8.06(s, 1H), 8.85(s, 1H)

Examples

The following compounds were obtained by treating ethyl2-(purin-6-ylthio)hexanoate with8-chloromethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine bythe same method as the one of Example 1094.

Ex. Structural formula NMR 1457

¹H-NMR(CDCl₃) δ ppm: 0.90(t, J=7Hz, 3H), 1.26(t, J=7Hz, 3H), 1.37(m,2H), 1.48(m, 2H), 1.97(m, 1H), 2.06(m, 1H), 3.43(s, 3H), 4.20(q, J=7Hz,2H), 4.88(t, J=7Hz, 1H), 5.17(s, 2H), 5.33(s, 2H), 6.83(d, J=8Hz, 1H),6.94(s, 1H), 6.97(d, J=8Hz, 1H), 7.83(m, 2H), 7.95(s, 1H), 8.75(s, 1H)1458

¹H-NMR(CDCl₃) δ ppm: 0.89(m, 3H), 1.25(t, J=7Hz, 3H), 1.35-1.46(m, 4H),1.97-2.06(m, 2H), 3.38(s, 3H), 4.15- 4.27(m, 1H), 4.86(t, J=7Hz, 2H),5.17(m, 2H), 5.45(d, J=10Hz, 1H), 5.59(d, J=10Hz, 1H), 6.75(d, J=8Hz,1H), 6.99(m, 2H), 7.84(m, 2H), 8.07(s, 1H), 8.82(s, 1H)

Examples

The following compounds were obtained by treating the compounds in theabove table by the same method as the one of Example 1450.

Ex. Structural formula MS M.p. NMR 1459

FAB (+) 480 (MH⁺) 110- 120° C. (dec) ¹H-NMR(DMSO-d₆) δ ppm: 0.84(t,J=7Hz, 3H), 1.19- 1.41(m, 4H), 1.80-2.00(m, 2H), 4.80(t, J=7Hz, 1H),5.30(s, 2H), 6.55(s, 1H), 6.74(d, J=8Hz, 1H), 6.87(d, J=8Hz, 1H),7.60(s, 2H), 8.56(s, 1H), 8.70(s, # 1H), 9.42(s, 1H) 1460

FAB (+) 506 (MH⁺) 152- 156° C. ¹H-NMR(CDCl₃) δ ppm: 0.91(t, J=7Hz, 3H),1.10(t, J=7Hz, 3H), 1.13-1.32(m, 4H), 1.72-1.95(m, 2H), 4.10(q, J=7Hz,2H), 4.79(t, J=8Hz, 1H), 5.25(d, J=16Hz, 1H), 5.37(d, J=16Hz, 1H),6.42(s, 1H), 6.53(d, J=8Hz, 1H), # 6.69(d, J=8Hz, 1H), 7.37(s, 1H),7.48(s, 1H), 7.95(s, 1H), 8.67(s, 1H)

Examples

The following compounds were obtained by treating methyl11-(purin-6-ylthio)undecanoate with8-chloromethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine bythe same method as the one of Example 1094.

Ex. Structural formula NMR 1461

¹H-NMR(CDCl₃) δ ppm: 1.23-1.35(m, 12H), 1.47(quint, J=7Hz, 2H),1.78(quint, J=7Hz, 2H), 2.30(t, J=7Hz, 2H), 3.38(t, J=7Hz, 2H), 3.43(s,3H), 3.66(s, 3H), 5.17(s, 2H), 5.34(s, 2H), 6.84(d, J=8Hz, 1H), 6.97(d,J=8Hz, 1H), 7.08(s, 1H), 7.82(d, J=3Hz, 1H), 7.83(d, # J=3Hz, 1H),7.94(s, 1H), 8.73(s, 1H) 1462

¹H-NMR(CDCl₃) δ ppm: 1.24-1.36(m, 12H), 1.41(m, 2H), 1.71(quint, J=7Hz,2H), 2.39(t, J=7Hz, 2H), 3.35(s, 3H), 3.37(t, J=7Hz, 2H), 3.66(s, 3H),5.12(s, 2H), 5.58(s, 2H), 6.73(d, J=8Hz, 1H), 6.87(s, 1H), 6.99(d,J=8Hz, 1H), 7.82-7.84(m, 2H), 8.06(s, 1H), 8.85(s, 1H)

Examples

The following compounds were obtained by treating the compounds in theabove table by the same method as the one of Example 1450.

Ex. Structural formula MS M.p. NMR 1463

FAB (+) 550 (MH⁺) 154- 156° C. ¹H-NMR(DMSO- d₆) δ ppm: 1.20-1.30(m,10H), 1.35-1.50 (m, 4H), 1.70(m, 2H), 2.16(t, J= 7Hz, 2H), 3.37(t,J=7Hz, 2H), 5.30(s, 2H), 6.55(d, J=1Hz, 1H), 6.73(dd, J=1, 8Hz, # 1H),6.87(d, J=8Hz, 1H), 7.61(s, 2H), 8.52(s, 1H), 8.69 (s, 1H), 9.43(s, 1H)1464

FAB (+) 549 (M⁺) 166- 170° C. ¹H-NMR(DMSO- d₆) δ ppm: 1.02-1.30(m, 12H),1.42(quint, J=7Hz, 2H), 1.57(quint, J= 7Hz, 2H), 2.13(t, J=7Hz, 2H),3.35(t, J=7Hz, 2H), 5.55(s, 2H), 6.30(s, 1H), 6.55 (d, # J=8Hz, 1H),6.76(d, J=8Hz, 1H), 7.58(d, J= 3Hz, 1H), 7.59(d, J=3Hz, 1H), 8.67(s,1H), 8.75 (s, 1H), 9.36(s, 1H)

Examples

The following compounds were obtained by treating8-chloromethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]-benzothiazinewith various purine compounds by the same method as the one of Example1094.

Purine Ex. derivative Structural formula 1465

1466

1467

Ex. NMR 1465 ¹H-NMR(CDCl₃) δ ppm: 1.26(t, J=7Hz, 3H), 2.87(t, J=7Hz,2H), 3.43(s, 3H), 3.64(t, J=7Hz, 2H), 4.17(t, J=7Hz, 2H), 5.23(s, 2H),5.32(s, 2H), 6.82(d, J=8Hz, 1H), 6.96(d, J=8Hz, 1H), 7.27(s, 1H),7.82(m, 2H), 7.95(s, 1H), 8.76(s, 1H) 1466 ¹H-NMR(CDCl₃) δ ppm: 3.41(s,3H), 3.89(s, 3H), 4.68(s, 2H), 5.17(s, 2H), 5.34(s, 2H), 6.85(dd, J=2,8Hz, 1H), 6.97(d, J=8Hz, 1H), 7.08(d, J=2Hz, 1H), 7.37(t, J=8Hz, 1H),7.68(td, J=1, 8Hz, 1H), 7.83(d, J=3Hz, 1H), 7.85(d, J=3Hz, 1H), 7.91(td,J=1, 8Hz, 1H), 7.96(s, 1H), 8.16(t, J=1Hz, 1H), 8.78(s, 1H) 1467¹H-NMR(CDCl₃) δ ppm: 1.24(t, J=7Hz, 3H), 1.53(m, 2H), 1.68(quint, J=7Hz,2H), 1.81(quint, J=7Hz, 2H), 2.32(t, J=7Hz, 2H), 3.39(t, J=7Hz, 2H),3.43(s, 3H), 4.12(q, J=7Hz, 2H), 5.23(s, 2H), 5.34(s, 2H), 6.86(dd, J=2,8Hz, 1H), 6.96(d, J=8Hz, 1H), 7.10(d, J=2Hz, 1H), 7.80(d, J=3Hz, 1H),7.82(d, J=3Hz, 1H), 7.94(s, 1H), 8.72(s, 1H)

Examples

The following compounds were obtained by treating the compounds in theabove table by the same method as the one of Example 1450.

Ex. Structural formula MS M.p. NMR 1468

¹H-NMR(DMSO-d₆) δ ppm: 2.55(t, J=7Hz, 2H), 3.35(t, J=7Hz, 2H), 5.74(s,2H), 6.55(d, J=1Hz, 1H), 6.73(dd, J=1, 8Hz, 1H), 6.87(d, J=8Hz, 1H),7.61(s, 2H), 8.54(s, 1H), 8.72(s, 1H), 9.43(s, 1H) 1469

FAB (+) 514 (MH⁺) ¹H-NMR(CDCl₃) δ ppm: 3.90(s, 3H), 4.70(s, 2H), 5.25(s,2H), 6.38(d, J=1Hz, 1H), 6.40(br.s, 1H), 6.76(dd, J=1, 8Hz, 1H), 6.86(d,J=8Hz, 1H), 7.37(t, J=8Hz, 1H), 7.57(d, J=3Hz, 1H), 7.68(td, J=1, 8Hz,1H), 7.70(d, J=3Hz, 1H), 7.91(td, # J=1, 8Hz, 1H), 7.94(s, 1H), 8.15(t,J=1Hz, 1H), 8.77(s, 1H) 1470

FAB (+) 480 (MH⁺) ¹H-NMR(DMSO-d₆) δ ppm: 1.41(quint, J=7Hz, 2H),1.52(quint, J=7Hz, 2H), 1.69(quint, J=7Hz, 2H), 2.20(t, J=7Hz, 2H),3.35(t, J=7Hz, 2H), 5.30(s, 2H), 6.55(d, J=1Hz, 1H), 6.74(dd, J=1, 8Hz,1H), 6.87(d, J=8Hz, 1H), 7.61(s, 2H), # 8.53(s, 1H), 8.69(s, 1H),9.43(s, 1H), 11.9(s, 1H) 1471

FAB (+) 508 (MH⁺) 78- 79° C. ¹H-NMR(CDCl₃) δ ppm: 1.16(t, J=7Hz, 3H),1.35(quint, J=7Hz, 2H), 1.65(quint, J=7Hz, 2H), 1.81(quint, J=7Hz, 2H),2.31(t, J=7Hz, 2H), 3.40(t, J=7Hz, 2H), 4.12(q, J=7Hz, 2H), 5.25(s, 2H),6.39(s, 2H), 6.74(d, # J=8Hz, 1H), 6.85(d, J=8Hz, 1H), 7.55(s, 1H),7.70(s, 1H), 7.94(s, 1H), 8.73(s, 1H)

Example 1472[9-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)purin-6-yl]carbothioamide

In a steel container, 2.75 g of9-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)purine-6-carbonitrileand 6.5 g of powdery sodium hydrogensulfide were suspended in 150 ml ofmethanol. Next, hydrogen sulfide was blown into the system at −30° C. toensure saturation thereof and then the container was hermeticallysealed. After heating the reactor to 80 to 90° C. for 4 hours, thereaction mixture was poured into an aqueous solution of potassiumhydrogensulfate. The crystals thus precipitated were taken up byfiltration and washed with water. Thus, 3.1 g of the title compound wasobtained as yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 5.48(s, 2H), 6.66(s, 1H), 6.75(d, J=8.3 Hz, 1H),6.88(d, J=8.3 Hz, 1H), 7.61(s, 2H), 8.75(s, 1H), 8.92(s, 1H), 9.47(s,1H), 9.90-10.03(br.s, 1H), 10.38-10.51(br.s, 1H)

Example 1473[9-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)purin-6-yl]-N²-cyanocarboxamidine

500 mg of[9-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)purin-6-yl]carbothioamidewas dissolved in a solvent mixture of acetone (200 ml) withN,N-dimethylformamide (10 ml). Under ice-cooling, 300 mg of methyliodide was added thereto and the resulting mixture was stirred at 0° C.to room temperature for 3 hours. Then the reaction mixture wasdistributed into an aqueous solution of potassium carbonate and ethylacetate and the organic layer was extracted. After distilling off thesolvent under reduced pressure, the residue was dissolved in drymethanol (5 ml) and tetrahydrofuran (10 ml). After adding 1.0 g ofcyanamide, the reaction mixture was stirred at 30 to 40° C. for 3 hours.Then the reaction mixture was distributed into water and ethyl acetate.The organic layer was extracted, washed with water and dried overanhydrous sodium sulfate. After distilling off the solvent under reducedpressure, the residue was purified by silica gel column chromatography(eluted with dichloromethane/methanol) to thereby give 78 mg of thetitle compound as yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 5.40(s, 2H), 6.53-6.70(br.s, 1H), 6.76(d, J=7.9Hz, 1H), 6.88(d, J=7.9 Hz, 1H), 7.61(s, 2H), 8.89(s, 1H),9.03-9.10(br.s, 1H), 9.30-9.50(m, 3H)

MS: FAB(+)400(M⁺)

m.p.: >290° C.

Example 1474N²-[9-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)purin-6-yl]-N¹,N¹-dimethylformamidine

The title compound was obtained by treating8-(6-aminopurin-9-yl)-10H-pyrazino[2,3-b][1,4]benzothiazine withN,N-dimethylformamide dimethyl acetal by the same method as the one ofExample 1540.

¹H-NMR(DMSO-d₆) δ ppm: 3.11(s, 3H), 3.17(s, 3H), 3.24(s, 2H), 6.58(s,1H), 6.70(d, J=8 Hz, 1H), 6.86(d, J=8 Hz, 1H), 7.61(s, 2H), 8.31(s, 1H),8.39(s, 1H), 8.90(s, 1H), 9.47(s, 1H)

Example 1475 8-(6-Aminopurin-9-yl)-10H-pyrazino[2,3-b][1,4]benzothiazinehemioxalate

The title compound was obtained by hydrogenating9-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)purine-6-carbonitrileby the same method as the one of Example 16.

¹H-NMR(DMSO-d₆) δ ppm: 4.58(br.s, 2H), 5.37(s, 2H), 6.68(s, 1H), 6.71(d,J=8 Hz, 1H), 6.88(d, J=8 Hz, 1H), 7.62(s, 2H), 8.61(br.s, 3H), 8.79(s,1H), 8.99(s, 1H), 9.50(s, 1H)

MS: ESI(+)363(MH⁺)

m.p.: 97-104° C.(dec)

Example 1476N¹-[9-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)purin-6-ylmethy]-N²-cyanoformamidine

The title compound was obtained by treating8-(6-aminomethylpurin-9-yl)-10H-pyrazino[2,3-b][1,4]benzothiazine withethyl N-cyanoformimidate by the same method as the one of Example 1534.

¹H-NMR(DMSO-d₆) δ ppm: 5.24(s, 2H), 6.30(s, 2H), 6.60(s, 1H), 6.74(d,J=8 Hz, 2H), 6.87(d, J=8 Hz, 1H), 7.62(s, 2H), 8.48(s, 1H), 8.69(s, 1H),8.88(s, 1H), 9.46(s, 1H)

Example 1477 (10H-Pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbonitrile

150 mg of the title compound was obtained by treating 300 mg of(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbonitrileby the same method as the one of Example 434.

¹H-NMR(DMSO-d₆) δ ppm: 6.96(d, J=1.8 Hz, 1H), 7.10(dd, J=1.8, 8.2 Hz,1H), 7.18(d, J=8.2 Hz, 1H), 7.67(d, J=3.3 Hz, 1H), 7.68(d, J=3.3 Hz,1H), 9.74(s, 1H)

MS: FAB(+)227(MH⁺)

m.p.: 263-264° C.

Example 1478 (10H-Pyrazino[2,3-b][1,4]benzothiazin-8-yl)carboxamidinehydrochloride

Into a metallic pressure container (50 ml) were fed 300 mg of(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbonitrile and 450 mg ofammonium chloride. After adding about 20 ml of liquefied ammonia at −78°C., the container was sealed and heated to 120° C. for 15 hours. Then itwas opened under ice-cooling and the ammonia was released. The obtainedresidue was distributed into dilute hydrochloric acid and ethyl acetate.The aqueous layer was washed with ethyl acetate several times. Then thepH value of the aqueous layer was adjusted to about 10 with potassiumhydroxide. Next, it was extracted with ethyl acetate and dried overanhydrous potassium carbonate. After distilling off the solvent underreduced pressure, the obtained residue was dissolved in a small amountof methanol. After adding hydrogen chloride and ethyl acetate,crystallization was effected to thereby give 45 mg of the title compoundas orange crystals.

¹H-NMR(DMSO-d₆) δ ppm: 6.99(s, 1H), 7.09(d, J=8.0 Hz, 1H), 7.14(d, J=8.0Hz, 1H), 7.70(d, J=2.8 Hz, 1H), 7.71(d, J=2.8 Hz, 1H), 9.10(br.s, 2H),9.31(br.s, 2H), 9.82(br.s, 1H)

MS: FAB(+)244(MH⁺)

m.p.: >280° C.

Example 1479 (10H-Pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetamidine

2.68 g of ammonium chloride was added to 20 ml of dry toluene in anitrogen atmosphere. Then 36.5 ml of a 15% solution of trimethylaluminumin n-hexane was added thereto under stirring and ice-cooling. Thereaction mixture was brought back to room temperature and 70 ml of drytoluene was further added. The resulting mixture was subjected toultrasonication until the ammonium chloride disappeared completely. A 60ml portion of the solution thus obtained was taken and 1.5 g of(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetonitrile was addedthereto. The obtained mixture was heated under reflux for 18 hours.After bringing back to room temperature, the reaction mixture wasdistributed into ethyl acetate and dilute hydrochloric acid andrepeatedly extracted with water. The aqueous layer was washed withmethylene chloride and the solvent contained in the solution waseliminated under reduced pressure. The obtained residue was purified byHigh-porous gel column chromatography (CHP20, mfd. by MitsubishiChemical Industries, Ltd., 75-15μ) (eluted with water/methanol) tothereby give 620 mg of the title compound as yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 3.52(br.s, 2H), 6.70(br.s, 1H), 6.75(br.d, J=8.0Hz, 1H), 6.91(br.d, J=8.0 Hz, 1H), 7.64(br.s, 2H)

Example 1480 (10H-Pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetamidinehydrochloride

(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-yl) acetamidine was dissolved ina small amount of methanol and a solution of hydrogen chloride in ethylacetate was added thereto under ultrasonication. Thus, the titlecompound was obtained almost quantitatively as the precipitated orangecrystals.

¹H-NMR(DMSO-d₆) δ ppm: 3.56(s, 2H), 6.71(s, 1H), 6.79(d, J=8.2 Hz, 1H),6.91(d, J=8.2 Hz, 1H), 7.64(s, 2H), 8.76(br.s, 2H), 9.18(br.s, 2H),9.65(s, 1H)

MS: FAB(+)258(MH⁺)

m.p.: >280° C.

Examples

The following compounds were obtained by the same method as the one ofExample 1479 by using methylamine hydrochloride and dimethylaminehydrochloride each as a substitute for the ammonium chloride followed bythe same treatment as the one of Example 1399.

Ex. Structural formula MS M.p. NMR 1481

FAB (+) 272 (MH⁺) 244- 247° C. ¹H-NMR(DMSO-d₆) δ ppm: 2.81(s, 3H),3.59(s, 2H), 6.69(s, 1H), 6.78(d, J=8.1Hz, 1H), 6.91(d, J=8.1Hz, 1H),7.64(s, 2H), 8.72- 8.83(br.s, 1H), 9.26- 9.37(br.s, 1H), 9.62(s, 1H),9.76-9.86(br.s, 1H) 1482

FAB (+) 286 (MH⁺) >280° C. ¹H-NMR(DMSO-d₆) δ ppm: 3.05(s, 3H), 3.07(s,3H), 3.84(s, 2H), 6.66(s, 1H), 6.71(d, J=8.2Hz, 1H), 6.92(d, J=8.2Hz,1H), 7.64(s, 2H), 8.79-8.87(br.s, 1H), 9.43-9.50(br.s, 1H), 9.60(s, 1H)

Example 1483Methyl(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetothioimidate

Into 15 ml of a solution of 318 mg of(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)thioacetamidein acetone was dropped 1.5 m of methyl iodide. After stirring at roomtemperature for 2 hours, the reaction mixture was distributed into ethylacetate and an aqueous solution of potassium carbonate. The organiclayer was extracted and the extract was washed with water and dried overanhydrous sodium sulfate. After distilling off the solvent under reducedpressure, 350 mg of the title compound was obtained as a yellow oilysubstance.

¹H-NMR(CDCl₃) δ ppm: 2.29(br.s, 3H), 3.53(s, 3H), 3.68(s, 2H), 5.27(s,2H), 6.88(br.d, J=7.7 Hz, 1H), 6.98(d, J=7.7 Hz, 1H), 7.04(br.s, 1H),7.83(d, J=2.8 Hz, 1H), 7.84(d, J=2.8 Hz, 1H)

Example 1484N-Phenyl-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]-benzothiazin-8-yl)acetamidine

350 mg ofmethyl(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetothioimidatewas dissolved in a solvent mixture of tetrahydrofuran (7 ml) withmethanol (15 ml). After adding 0.5 ml of aniline, the resulting mixturewas heated under reflux for 5 hours. Then the reaction mixture wasbrought back to room temperature. After distilling off the solvent underreduced pressure, the residue was purified by silica gel columnchromatography (eluted with dichloromethane/methanol/aqueous ammonia) tothereby give 250 mg of the title compound as yellow crystals.

¹H-NMR(CDCl₃) δ ppm: 3.53(s, 3H), 3.60(s, 2H), 3.6-4.1(br.s, 2H),5.24(s, 2H), 6.92(d, =7.3 Hz, 2H), 6.94(br.d, J=7.7 Hz, 1H), 6.98(d,J=7.7 Hz, 1H), 7.04(t, J=7.3 Hz, 1H), 7.17(br.s, 1H), 7.31(t, J=7.3 Hz,2H), 7.83(d, J=2.7 Hz, 1H), 7.84(d, J=2.7 Hz, 1H)

Example 1485N-Phenyl-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetamidinehydrochloride

250 mg ofN-phenyl-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetamidinewas treated by the same method as the one of Example 434 and thencrystallized from ethyl acetate containing hydrogen chloride. Thus, 130mg of the title compound was obtained as orange crystals.

¹H-NMR(DMSO-d₆) δ ppm: 3.78(s, 2H), 6.81(s, 1H), 6.86(d, J=8.2 Hz, 1H),6.95(d, J=8.2 Hz, 1H), 7.32(d, J=7.4 Hz, 2H), 7.44(t, J=7.4 Hz, 1H),7.53(t, J=7.4 Hz, 2H), 7.64(d, J=2.2 Hz, 1H), 7.65(d, J=2.2 Hz, 1H),8.76(s, 1H), 9.67-9.75(br.s, 1H), 9.70(s, 1H), 11.66(s, 1H)

MS: FAB(+)334(MH⁺)

m.p.: 245-249° C.(decompose)

Example 1486Methyl(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetothioimidate

The title compound was obtained as a yellow oily substancequantitatively by treating(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)thioacetamide with methyliodide by the same method as the one of Example 1483.

¹H-NMR(DMSO-d₆) δ ppm: 2.61(s, 3H), 4.00(s, 2H), 6.68(s, 1H), 6.77(d,J=8.1 Hz, 1H), 6.94(d, J=8.1 Hz, 1H), 7.65(s, 2H), 9.62(s, 1H)

Example 1487N²-Cyano-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetamidine

To 15 ml of a solution of 410 mg of methyl(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetothioimidate in methanolwas added 250 mg of cyanamide and the resulting mixture was heated to60° C. or below for 1 hour. Then the reaction mixture was brought backto room temperature and the solvent was distilled off under reducedpressure to reduce its amount. The crystals thus precipitated were takenup by filtration and washed successively with methanol and ethylacetate. Thus, 295 mg of the title compound was obtained as yellowcrystals.

¹H-NMR(CD₃OD) δ ppm: 3.62(br.s, 2H), 6.67(br.s, 1H), 6.78(d, J=8 Hz,1H), 6.84(d, J=8 Hz, 1H), 7.57(d, J=3 Hz, 1H), 7.58(d, J=3 Hz, 1H)

MS: FAB(+)286(MH⁺)

m.p.: 230-232° C.

Examples

The following compounds were synthesized by treatingmethyl(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetothioimidate withvarious amines by the same method as the one of Example 1487.

Ex. Structural formula MS M.p. NMR 1488

FAB (+) 336 (MH⁺) ¹H-NMR(DMSO-d₆) δ ppm: 2.83(s, 3H), 3.33(s, 2H),6.70(s, 1H), 6.71(d, J=7.8Hz, 1H), 6.85(d, J=7.8Hz, 1H), 7.60-7.65(m,2H), 7.79(s, 1H), 8.58(s, 1H), 9.57(s, 1H) 1489

FAB (+) 390 (MH⁺), 389 (M⁺) 200- 202° C. ¹H-NMR(DMSO-d₆) δ ppm: 3.57(s,2H), 6.67(s, 1H), 6.70(d, J=7.5Hz, 1H), 6.89(d, J=7.5Hz, 1H), 7.61-7.66(m, 2H), 9.00- 9.10(br.s, 1H), 9.58(s, 1H), 9.63-9.72(br.s, 1H) 1490

FAB (+) 398 (MH⁺), 397 (M⁺) 206- 207° C. ¹H-NMR(DMSO-d₆) δ ppm: 3.34(s,2H), 6.62(d, J=7.8Hz, 1H), 6.66(s, 1H), 6.79(d, J=7.8Hz, 1H), 7.43-7.57(m, 3H), 7.61-7.69(m, 2H), 7.70-7.78(m, 2H), 8.00-8.10(br.s, 1H),8.73- 8.84(br.s, # 1H), 9.53(s, 1H) 1491

FAB (+) 296 (MH⁺) 222- 223° C. ¹H-NMR(DMSO-d₆) δ ppm: 3.48(t, J=2.5Hz,1H), 3.62(s, 2H), 4.15(dd, J=2.5, 5.4Hz, 2H), 6.71(s, 1H), 6.78(d,J=8.2Hz, 1H), 6.91(d, J=8.2Hz, 1H), 7.64(s, 2H), 9.11(s, 1H), 9.66(d,J=2.4Hz, 2H), 10.25(t, J=5.4Hz, 1H) 1492

FAB (+) 336 (M⁺) >260° C. (decom- pose) ¹H-NMR(DMSO-d₆) δ ppm: 3.51(s,2H), 4.3-4.5(br.s, 1H), 5.1-5.3(br.s, 1H), 6.70(br.s, 1H), 6.76(br.d,J=7.9Hz, 1H), 6.91(br.d, J=7.9Hz, 1H), 7.65(br.s, 2H) 1493

FAB (+) 413 (MH⁺) 226- 227° C. ¹H-NMR(DMSO-d₆) δ ppm: 3.03-3.10(br.s,2H), 6.09- 6.12(br.s, 1H), 6.50- 6.62(br.d, J=7.6Hz, 1H), 6.58(s, 1H),6.74(d, J=7.6Hz, 1H), 7.27- 7.42(br.s, 1H), 7.47- 7.59(m, 3H),7.60-7.66(m, 2H), 7.70-7.80(m, # 2H), 8.82-8.92(br.s, 1H), 9.43-9.55(br.s, 1H) 1494

FAB (+) 301 (MH⁺) ¹H-NMR(DMSO-d₆) δ ppm: 3.13 and 3.17(s, total 2H),6.03 and 6.10(s, total 1H), 6.67-6.77(m, 2H), 7.60- 7.63(m, 1H), 7.80(s,initial 1H), 8.33(d, J=9.8Hz, initial 1H), 9.47(s, 2H), 9.51(s, initial1H), 9.34(d, J=9.8Hz, initial 1H) 1495

FAB (+) 329 (MH⁺) 158- 161° C. ¹H-NMR(DMSO-d₆) δ ppm: 2.76(s, 3H),2.96(s, 3H), 3.23(s, 2H), 6.73(s, 1H), 6.74(d, J=7.9Hz, 1H), 6.82(d,J=7.9Hz, 1H), 7.61(d, J=2.3Hz, 1H), 7.62(d, J=2.3Hz, 1H), 7.82-8.00(br.s, 1H), 8.82- 9.04(br.s, 1H), 9.53(s, 1H) 1496

FAB (+) 287 (M⁺) 217- 218° C. ¹H-NMR(DMSO-d₆) δ ppm: 3.04(s, 2H),3.57(s, 3H), 5.57-5.63(br.s, 2H), 6.68(d, J=1.5Hz, 1H), 6.72(d, J=7.7Hz,1H), 6.82(dd, J=1.5, 7.7Hz, 1H), 7.61-7.64(m, 2H), 9.50(s, 1H) 1497

FAB (+) 273 (M⁺) 252- 254° C. ¹H-NMR(DMSO-d₆) δ ppm: 3.06(s, 2H), 5.30-5.36(br.s, 2H), 6.66(d, J=1.0Hz, 1H), 6.70(dd, J=1.0, 7.5Hz, 1H),6.81(d, J=7.5Hz, 1H), 7.61(d, J=2.3Hz, 1H), 7.62(d, J=2.3Hz, 1H),8.89(s, 1H), 9.49(s, 1H)

Example 1498N²-Cyano-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetamidine

500 mg of7-chloromethyl-10-methoxymethyhl-10H-pyrazino[2,3-b][1,4]benzothiazinewas treated by the same method as the one of Example 1513 to therebygive(10-methoxymethyhl-10H-pyrazino[2,3-b][1,4]benzothiazin-7-yl)acetonitrile.Next, this product was converted intomethyl(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-7-yl)acetimidateby the same method as the one of Example 1518. After treating withcyanamide by the same method as the one of Example 1487, 110 mg of thetitle compound was obtained as yellow crystals.

¹H-NMR(CD₃OD) δ ppm: 3.63(br.s, 2H), 6.62 and 6.64(d, J=8 Hz, 1H),6.81(d, J=2 Hz) and 6.86(br.s)(total 1H), 6.91(dd, J=2, 8 Hz) and6.97(d, J=8 Hz)(total 1H), 7.55 and 7.57(d, J=3 Hz, 1H), 7.56 and7.58(d, J=3 Hz, 1H)

MS: FAB(+)283(MH⁺)

m.p.: 218-219° C.

Example 1499N²-Cyano-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetamidine S-oxide

To a solution of 150 mg ofN²-cyano-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetamidine inacetic acid (10 ml) was added 1.0 ml of 30% hydrogen peroxide and theresulting mixture was heated to 40 to 45° C. for 30 minutes. Then 5 mlof an aqueous solution of 3 g of sodium thiosulfate was added to thereaction mixture. After distilling off the solvent under reducedpressure, the obtained residue was extracted by decantation withdichloromethane/methanol (20%). The extract was distilled under reducedpressure. The residue thus obtained was purified by silica gel columnchromatography (eluted with dichloromethane/methanol) to thereby give110 mg of the title compound as colorless crystals.

¹H-NMR(DMSO-d₆) δ ppm: 3.90(br.s, 2H), 7.22-7.30(m, 1H), 7.47-7.56(m,1H), 7.97-8.06(m, 1H), 8.50(d, J=2.1 Hz, 1H), 8.69(d, J=2.1 Hz, 1H)

MS: FAB(+)299(MH⁺)

m.p.: >280° C.

Examples

The following compounds were obtained by treatingmethyl(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetimidatehydrochloride with various amines.

Ex. Amine Structural formula MS M.p. NMR 1500

FAB (+) 298 (MH⁺) >280° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.76-1.90(m, 2H),3.23-3.40(m, 4H), 3.58(s, 2H), 6.69(d, J=1.5Hz, 1H), 6.78(dd, J=1.5,8.4Hz, 1H), 6.91(d, J=8.4Hz, 1H), 7.63(d, J=2.4Hz, 1H), 7.65(d, J=2.4Hz,1H), 9.61(s, 1H), 9.82-9.90(br.s, 2H) 1501

FAB (+) 302 (MH⁺) 174- 175° C. ¹H-NMR(DMSO-d₆) δ ppm: 3.26-3.33(m, 2H),3.53-3.59(m, 2H), 3.60(s, 2H), 5.07(t, J=5.0Hz, 1H), 6.69(d, J=1.5Hz,1H), 6.77(dd, J=1.5, 8.0Hz, 1H), 6.80(d, J=8.0Hz, 1H), 7.63(d, J=2.4Hz,1H), 7.64(d, J=2.4Hz, 1H), 8.74- 8.81(br.s, 1H), 9.16-9.23(br.s, 1H),9.62(s, 1H), 9.74-9.82(br.s, 1H) 1502

FAB (+) 312 (MH⁺) >280° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.91-2.00(m, 2H),2.99(s, 3H), 3.29- 3.36(m, 2H), 3.39- 3.46(m, 2H), 3.84(s, 2H), 6.68(d,J=1.2Hz, 1H), 6.73(dd, J=1.2, 8.1Hz, 1H), 6.92(d, J=8.1Hz, 1H), 7.65(s,2H), 9.59(s, 1H), 10.07- 10.12(br.s, 1H) 1503

FAB (+) 388 (MH⁺) 153- 155° C. (decom- pose) ¹H-NMR(DMSO-d₆) δ ppm:1.90-2.00(m, 2H), 3.26-3.32(m, 2H), 3.36-3.43(m, 2H), 3.96(s, 2H),4.57(s, 2H), 6.72(s, 1H), 6.77(d, J=7.8Hz, 1H), 6.89(d, J=7.8Hz, 1H),7.12- 7.18(m, 2H), 7.25- 7.37(m, 3H), 7.65(s, 2H), 9.56(s, 1H), 10.38-10.43(br.s, 1H) 1504

FAB (+) 314 (MH⁺) 156- 163° C. ¹H-NMR(DMSO-d₆) δ ppm: 3.15-3.22(m, 2H),3.31-3.38(m, 2H), 3.60(s, 2H), 4.08- 4.13(m, 1H), 5.51(d, J=3.7Hz, 1H),6.71(d, J=1.4Hz, 1H), 6.78(dd, J=1.4, 8.4Hz, 1H), 6.90(d, J=8.4Hz, 1H),7.63(d, J=2.0Hz, 1H), 7.65(d, J=2.0Hz, 1H), 9.62(s, 1H), 9.78-9.88(br.s, 2H) 1505

FAB (+) 391 (MH⁺) 275- 277° C. ¹H-NMR(DMSO-d₆) δ ppm: 3.20(s, 3H), 3.24-3.31(m, 2H), 3.45- 3.52(m, 2H), 3.60(s, 2H), 3.85-3.91(m, 1H), 6.72(s,1H), 6.80(d, J=7.5Hz, 1H), 6.91(d, J=7.5Hz, 1H), 7.58- 7.69(m, 1H),7.64(d, J=2.5Hz, 1H), 7.65(d, J=2.5Hz, 1H), 9.59(s, 1H) 1506

FAB (+) 420 (MH⁺) 251- 254° C. ¹H-NMR(DMSO-d₆) δ ppm: 2.66(s, 6H), 3.25-3.33(m, 3H), 3.42- 3.49(m, 2H), 3.56- 3.60(br.s, 2H), 3.70-3.76(m, 1H),6.71(d, J=1.4Hz, 1H), 6.80(dd, J=1.4, 7.8Hz, 1H), 6.91(d, J=7.8Hz, 1H),7.65(s, 2H), 9.59(s, 1H) 1507

FAB (+) 342 (MH⁺) 265- 267° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.18-1.43(m, 2H),1.55-1.85(m, 2H), 3.24-3.47(m, 2H), 3.57-3.82(m, 3H), 3.88(s, 2H),3.93(d, J=4.1Hz, 1H), 6.64(s, 1H), 6.71(d, J=7.8Hz, 1H), 6.91(d,J=7.8Hz, 1H), 7.64(s, 2H), 9.61(s, 1H) 1508

FAB (+) 454 (MH⁺) 219- 220° C. ¹H-NMR(DMSO-d₆) δ ppm: 0.76-0.90(m, 1H),1.01(d, J=7.0Hz, 3H), 1.06-1.20(m, 2H), 1.13(t, J=6.8Hz, 3H),1.26-1.39(m, 1H), 1.43-1.55(m, 2H), 1.55-1.66(m, 1H), 1.69-1.81(m, 1H),2.27-2.38(m, 1H), 3.00-3.12(m, 2H), 3.24-3.36(m, 1H), 3.71-3.82(m, 1H),3.83-3.88(br.s, # 2H), 4.01(q, J=6.8Hz, 2H), 4.08-4.19(m, 1H), 6.63(d,J=1.3Hz, 1H), 6.71(dd, J=1.3, 8.3Hz, 1H), 6.92(d, J=8.3Hz, 1H), 7.64(s,2H), 8.93- 9.03(br.s, 1H), 9.43-9.52(br.s, 1H), 9.61(s, 1H) 1509

FAB (+) 448 (MH⁺) 215- 218° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.20(m, 1H),1.38(m, 1H), 1.53-1.72(m, 1H), 1.72-1.83(m, 1H), 1.86-2.00(m, 1H),2.50-2.70(m, 1H), 2.62(s, 6H), 3.17-3.43(m, 2H), 3.67-3.80(m, 1H),3.87(br.s, 2H), 6.66(d, J=2.0Hz, 1H), 6.71(dd, J=2.0, 7.8Hz, 1H),6.92(d, J=7.8Hz, # 1H), 7.34(d, J=7.4Hz, 1H), 7.65(s, 2H),9.00-9.13(br.s, 1H), 9.50-9.58(br.s, 1H), 9.60(s, 1H) 1510

FAB (+) 369 (MH⁺) 268- 269° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.93-2.03(br.s,3H), 3.35-3.74(m, 8H), 3.87-3.96(br.s, 2H), 6.64(d, J=1.1Hz, 1H),6.73(dd, J=1.1, 8.4Hz, 1H), 6.93(d, J=8.4Hz, 1H), 7.65(s, 2H), 9.11-9.26(br.s, 1H), 9.59(s, 1H), 9.60- 9.74(br.s, 1H) 1511

FAB (+) 432 (MH⁺) 215- 218° C. ¹H-NMR(DMSO-d₆) δ ppm: 2.85 and 2.86(s,total 3H), 3.28-3.31 and 3.46-3.52(m, total 2H), 3.54- 3.65(m, 4H),3.65- 3.71 and 3.72- 3.79(m, total 2H), 6.66(s, 1H), 6.73(d, J=7.5Hz,1H), 6.93(d, J=7.5Hz, 1H), 7.64(s, 2H), 8.13 and 8.17(br.s, total 1H),9.22-9.28 and # 9.28-9.36(br.s, total 1H), 9.59(s, 1H), 9.73-9.83(br.s,1H)

Example 15124-[1-[1-Imino-2-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-ethyl]piperidin-4-yl]-2-methylbutanoicacid hydrochloride

The title compound was obtained by hydrolyzing ethyl4-[1-[1-imino-2-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)ethyl]piperidin-4-yl]-2-methylbutanoatehydrochloride by the same method as the one of Example 18.

¹H-NMR(DMSO-d₆) δ ppm: 0.83-1.01(m, 2H), 0.90(d, J=6.9 Hz, 3H),1.03-1.22(m, 3H), 1.33-1.51(m, 2H), 1.54-1.65(m, 2H), 1.94-2.05(m, 1H),2.80-2.94(m, 2H), 3.70-3.77(br.s, 2H), 3.94-4.09(m, 2H), 6.65(d, J=8.0Hz, 1H), 6.66(s, 1H), 6.86(d, J=8.0 Hz, 1H), 7.62(s, 2H),9.60-9.76(br.s, 1H)

MS: FAB(+)426(MH⁺)

m.p.: 166-171° C.

Example 1513 (5H-Pyrido[3,4-b][1,4]benzothiazin-7-yl)acetonitrile

The title compound was obtained by treating5-methoxymethyl-7-(chloromethyl)-5H-pyrido[3,4-b][1,4]benzothiazine bythe same method as the one of Example 53 and then deblocking by the samemethod as the one of Example 8.

¹H-NMR(CDCl₃) δ ppm: 3.61(s, 2H), 6.18(br.s, 1H), 6.39(d, J=6 Hz, 1H),6.56(br.s, 1H), 6.78(d, J=8 Hz, 1H), 6.95(d, J=8 Hz, 1H), 7.98(s, 1H),8.08(d, J=6 Hz, 1H)

Examples

The following compounds were obtained by treating(5H-pyrido[3,4-b][1,4]benzothiazin-7-yl)acetonitrile by the same methodas the one of Example 1518 and treating the corresponding imidates thusobtained with various amines by the same method as the one of Example1520.

Ex. Amine Structural formula NMR 1514 H₂N—CN

¹H-NMR(D₂O) δ ppm: 3.51(s, 2H), 6.40(d, J=6Hz, 1H), 6.44(d, J=2Hz, 1H),6.63(d, J=8Hz, 1H), 6.70(dd, J=2, 8Hz, 1H), 7.52(d, J=1Hz, 1H), 7.63(dd,J=1, 6Hz, 1H) 1515

¹H-NMR(D₂O) δ ppm: 3.44-3.53(m, 6H), 3.68(t, J=5Hz, 2H), 3.75(s, 2H),6.44-6.48(m, 2H), 6.70(d, J=9Hz, 1H), 6.75(d, J=9Hz, 1H), 7.56(s, 2H),7.70(d, J=6Hz, 1H) 1516

¹H-NMR(D₂O) δ ppm: 1.72-2.34(m, 3H), 3.40- 3.78(m, 6H), 6.38-6.48(m,2H), 6.63-6.77(m, 2H), 7.52-7.57(m, 1H), 7.63- 7.70(m, 1H)

Example 1517 (10H-Pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetonitrile

The title compound was obtained from8-chloromethyl-10H-pyrazino[2,3-b][1,4]benzothiazine by the same methodas the one of Example 53.

¹H-NMR(DMSO-d₆) δ ppm: 3.88(s, 2H), 6.73(d, J=7.6 Hz, 1H), 6.74(s, 1H),6.91(d, J=7.6 Hz, 1H), 7.65(s, 2H), 9.60(s, 1H)

Example 1518Methyl(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetimidatehydrochloride

480 mg of (10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetonitrile wassuspended in a solution of dry methanol (20 ml)/dry dichloromethane andcooled to −20° C. Then dry hydrogen chloride gas was blown thereintountil saturation was attained while paying attention lest the bulktemperature exceed 0° C. Then the reaction mixture was hermeticallysealed and allowed to stand under ice-cooling over day and night. Next,the solvent was distilled off under reduced pressure while maintainingthe bulk temperature at room temperature or below. Then a small amountof dry methanol was added to the residue and ethyl acetate was graduallyadded thereto under ultrasonication. The orange crystals thusprecipitated were taken up by filtration, washed with diethyl ether anddried under reduced pressure. Thus, 570 mg of the title compound wasobtained.

¹H-NMR(DMSO-d₆) δ ppm: 3.85(s, 2H), 4.05(s, 3H), 6.69(s, 1H), 6.77(d,J=7.9 Hz, 1H), 6.90(d, J=7.9 Hz, 1H), 7.00-7.25(br.s, 2H), 7.53(s, 2H),9.61(s, 1H)

Example 1519 MethylN²-cyano(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetimidate

To 40 ml of an aqueous solution of 1.4 g of monosodiumdihydrogenphosphate, 3.2 g of disodium monohydrogenphosphate and 5 g ofcyanamide was added 20 ml of acetonitrile. To the obtained solution wasgradually added 30 ml of a suspension of 1.2 g ofmethyl(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetimidatehydrochloride in acetonitrile. The pH value of the reaction mixture wasstrictly adjusted to 6.0 to 6.5 by adding aqueous solutions ofmonosodium dihydrogenphosphate and disodium monohydrogenphosphaterespectively. After further adding about 100 ml of acetonitrile, thereaction mixture was stirred at room temperature for 30 minutes and thendistributed into an aqueous solution of ammonium chloride and ethylacetate. The organic layer was extracted, washed with water and driedover anhydrous sodium sulfate. After distilling off the solvent underreduced pressure, 1.2 g of the title compound was obtained as a yellowoily substance almost quantitatively.

¹H-NMR(CDCl₃) δ ppm: 3.77(s, 2H), 3.87(s, 3H), 6.50(d, J=1.8 Hz, 1H),6.75(dd, J=1.8, 8.2 Hz, 1H), 6.81(d, J=8.2 Hz, 1H), 7.09(br.s, 1H),7.57(d, J=3.2 Hz, 1H), 7.68(d, J=3.2 Hz, 1H)

Example 1520N¹-Methyl-N²-cyano(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetamidine

To 10 ml of a solution of 420 mg of methylN²-cyano(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetimidate intetrahydrofuran was added 1 ml of a 40% aqueous solution of methylamineand the resulting mixture was stirred at room temperature for 5 minutes.Then the reaction mixture was distributed into water and ethyl acetate.The organic layer was extracted, washed with water and dried overanhydrous sodium sulfate. After adding 3 g of silica gel, the solventwas distilled off under reduced pressure. The residue thus obtained waspurified by silica gel column chromatography (eluted withdichloromethane/methanol/aqueous ammonia) to thereby give 340 mg of thetitle compound as yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 2.72(s, 3H), 3.64(s, 2H), 6.68(s, 1H), 6.71(d,J=7.3 Hz, 1H), 6.88(d, J=7.3 Hz, 1H), 7.64(s, 2H), 8.86-8.93(br.s, 1H),9.58(s, 1H)

MS: FAB(+)297(MH⁺)

m.p .: 233-234° C.(decompose)

Examples

The following compounds were obtained by reacting methyl N²-cyano(10H-pyrazino [2,3-b][1,4]benzothiazin-8-yl)acetimidate with variousamines by the same method as the one of Example 1520.

Ex. Amine Structural formula MS M.p. NMR 1521

FAB (+) 311 (MH⁺) 247- 249° C. (decom- pose) ¹H-NMR(DMSO-d₆) δ ppm:3.02(s, 3H), 3.04(s, 3H), 3.95(s, 2H), 6.62(d, J=1.7Hz, 1H), 6.65(d,J=7.9Hz, 1H), 6.91(dd, J=1.7, 7.9Hz, 1H), 7.64(s, 2H), 9.54(s, 1H) 1522

FAB (+) 325 (MH⁺) 266- 268° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.12(d, J=6.8Hz,6H), 3.60(s, 2H), 3.87- 3.99(m, 1H), 6.67(d, J=1.7Hz, 1H), 6.69(dd,J=1.7, 7.5Hz, 1H), 6.88(d, J=7.5Hz, 1H), 7.63(d, J=2.4Hz, 1H), 7.64(d,J=2.4Hz, 1H), 8.93(d, J=7.9Hz, 1H), 9.66(s, 1H) 1523

FAB (+) 374 (MH⁺) 195- 196° C. ¹H-NMR(DMSO-d₆) δ ppm: 3.75(s, 2H),4.50(s, 2H), 6.75(s, 1H), 6.78(d, J=7.9Hz, 1H), 6.90(d, J=7.9Hz, 1H),7.27-7.32(m, 1H), 7.29(d, J=7.8Hz, 1H), 7.63-7.66(m, 2H), 7.77(d,J=7.8Hz, 1H), 8.52(d, J=6.0Hz, 1H), 9.45-9.55(m, 1H), 9.62(s, 1H) 1524

FAB (+) 327 (MH⁺) 268- 270° C. ¹H-NMR(DMSO-d₆) δ ppm: 3.23-3.29(m, 2H),3.46- 3.52(m, 2H), 3.66(s, 2H), 4.83(t, J=5.4Hz, 1H), 6.69(d, J=1.0Hz,1H), 6.72(dd, J=1.0, 8.4Hz, 1H), 6.88(d, J=8.4Hz, 1H), 7.63(d, J=2.6Hz,1H), 7.64(d, J=2.6Hz, 1H), 9.05(t, J=5.1Hz, 1H), 9.59(s, 1H) 1525

FAB (+) 413 (MH⁺), 435 (MNa+) 213- 215° C. ¹H-NMR(DMSO-d₆) δ ppm:2.65(t, J=7.4Hz, 2H), 3.39-3.46(m, 2H), 3.62(s, 2H), 6.69(s, 1H),6.71(d, J=7.7Hz, 1H), 6.86(d, J=7.7Hz, 1H), 7.60-7.65(m, 2H), 8.96(t,J=5.6Hz, 1H), 9.54(s, 1H) 1526

FAB (+) 396 (M⁺) 154- 155° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.16(t, J=6.9Hz,3H), 1.68-1.78(m, 2H), 2.31(t, J=7.6Hz, 2H), 3.16-3.24(m, 2H), 3.63(s,2H), 4.03(q, J=6.9Hz, 2H), 6.69(d, J=1.6Hz, 1H), 6.71(dd, J=1.6, 7.8Hz,1H), 6.89(d, J=7.8Hz, 1H), 7.63(d, J=2.4Hz, 1H), 7.64(d, J=2.4Hz, 1H),8.97(t, J=5.0Hz, 1H), 9.62(s, 1H) 1527

FAB (+) 452 (MH⁺) 241- 245° C. ¹H-NMR(DMSO-d₆) δ ppm: 3.72(s, 2H),4.47(d, J=5.6Hz, 2H), 6.74(d, J=8.1Hz, 1H), 6.75(s, 1H), 6.91(d,J=8.1Hz, 1H), 7.28-7.36(br.s, 2H), 7.43(d, J=7.8Hz, 2H, 7.64(d, J=2.4Hz,1H), 7.66(d, J=2.4Hz, 1H), 7.78(d, J=7.8Hz, 2H), 9.46(t, J=5.6Hz, 1H),9.66(s, 1H) 1528 H₂N—OH

FAB (+) 298 (M⁺) 253- 256° C. ¹H-NMR(DMSO-d₆) δ ppm: 3.58(s, 2H),6.64(d, J=1.1Hz, 1H), 6.68(dd, J=1.1, 8.4Hz, 1H), 6.82(d, J=8.4Hz, 1H),7.61(d, J=2.2Hz, 1H), 7.63(d, J=2.2Hz, 1H), 7.66-7.71(br.m, 2H), 9.47(s,1H) 1529 H₂N—OMe

FAB (+) 312 (M⁺) 172- 174° C. ¹H-NMR(DMSO-d₆) δ ppm: 3.43-3.46(br.s,2H), 3.73(s, 3H), 6.13- 6.25(br.s, 1H), 6.67(d, J=8.0Hz, 1H), 6.68(s,1H), 6.87(d, J=8.0Hz, 1H), 7.63(d, J=2.0Hz, 1H), 7.64(d, J=2.0Hz, 1H),9.57(s, 1H) 1530 H₂N—NH₂

FAB (+) 297 (M⁺) ¹H-NMR(DMSO-d₆) δ ppm: 3.53(s, 2H), 5.50- 5.80(br.s,2H), 6.63(s, 1H), 6.65(d, J=8.5Hz, 1H), 6.78(d, J=8.5Hz, 1H), 7.60(d,J=2.2Hz, 1H), 7.61(d, J=2.2Hz, 1H), 9.36-9.55(br.s, 1H) 1531

FAB (+) 410 (MH⁺) >280° C. ¹H-NMR(DMSO-d₆) δ ppm: 0.91(d, J=6.7Hz, 12H),2.43-2.49(m, 2H), 2.90(sept, J=6.7Hz, 2H), 3.09-3.17(m, 2H), 3.65(s,2H), 6.69(d, J=1.1Hz, 1H), 6.72(dd, J=1.1, 8.2Hz, 1H), 6.89(d, J=8.2Hz,1H), 7.63(d, J=2.4Hz, 1H), 7.65(d, J=2.4Hz, 1H), 8.63(br.t, J=5.7Hz,1H), 9.57-9.64(br.s, 1H) 1532

FAB (+) 391 (MH⁺) 205- 208° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.86-1.98(m, 2H),3.10- 3.16(m, 2H), 3.64(s, 2H), 3.97(t, J=7.1Hz, 2H), 6.69(s, 1H),6.72(d, J=8.6Hz, 1H), 6.87(s, 1H), 6.89(d, J=8.6Hz, 1H), 7.14(s, 1H),7.56(s, 1H), 7.62- 7.65(m, 2H), 9.00(t, J=5.4Hz, 1H), 9.63(s, 1H)

Example 15334-[[1-(N-Cyanoimino)-2-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)ethy]amino]butanoicacid

The title compound was obtained by hydrolyzing ethyl4-[N¹-[1-(N²-cyanoimino)-2-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)ethy]amino]butanoateby the same method as the one of Example 18.

¹H-NMR(DMSO-d₆) δ ppm: 1.65-1.76(m, 2H), 2.24(t, J=7.5 Hz, 2H),3.16-3.23(m, 2H), 3.63(s, 2H), 6.69(d, J=7.8 Hz, 1H), 6.71(dd, J=1.7,7.8 Hz, 1H), 6.89(d, J=1.7 Hz, 1H), 7.62(d, J=2.5 Hz, 1H), 7.64(d, J=2.5Hz, 1H), 8.99(t, J=5.4 Hz, 1H), 9.62(s, 1H), 12.11(s, 1H)

MS: FAB(+)369(MH⁺)

m.p.: 217-218° C.(decompose)

Example 1534N²-Cyano-N¹-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)formamidine

500 mg of 8-aminomethyl-10H-pyrazino[2,3-b][1,4]benzothiazine and 400 mgof ethyl N²-cyanocarboxyimidate were dissolved in a solvent mixture oftetrahydrofuran (5 ml) with methanol (5 ml) and stirred at 40° C. for1.5 hours. Then the reaction mixture was distributed into an aqueoussolution of potassium carbonate and ethyl acetate. The organic layer wasextracted, washed with water and dried over anhydrous sodium sulfate.After distilling off the solvent under reduced pressure, the obtainedresidue was purified by silica gel column chromatography (eluted withdichloromethane/methanol) and recrystallized from methanol/ethylacetate. Thus, 170 mg of the title compound was obtained as yellowcrystals.

¹H-NMR(DMSO-d₆) δ ppm: 4.20(d, J=5 Hz, 2H), 6.66(s, 1H), 6.68(d, J=8.0Hz, 1H), 6.87(d, J=8.0 Hz, 1H), 7.63(s, 2H), 8.41(d, J=4.4 Hz, 1H),9.30-9.38(m, 1H), 9.54(s, 1H)

MS: FAB(+)282(M⁺)

m.p.: 224-226° C.

Examples

The following compounds were obtained by treating8-(aminomethyl)-10-methoxymethyl-10H- pyrazino[2,3-b][1,4]benzothiazinewith various imidates by the same method as the one of Example 1534followed by deblocking in accordance with Example 9.

Ex. Imidate Structural formula MS M.p. NMR 1535

FAB(+) 296 (M⁺) 275- 277° C. ¹H-NMR(DMSO-d₆) δ ppm: 2.22(s, 3H), 4.18(d,J=5.8Hz, 2H), 6.66(s, 1H), 6.68(d, J=7.7Hz, 1H), 6.87(d, J=7.7Hz, 1H),7.59-7.66(m, 2H), 9.19(t, J=5.8Hz, 1H), 9.52(s, 1H) 1536

FAB(+) 335 (M⁺) 175- 176° C. ¹H-NMR(DMSO-d₆) δ ppm: 2.86(s, 3H), 4.24(s,2H), 6.68(s, 1H), 6.71(d, J=7.6Hz, 1H), 6.88(d, J=7.6Hz, 1H), 7.63(s,2H), 8.06(d, J=4.0Hz, 1H), 9.02(br.d, J=4.0Hz, 1H), 9.56(s, 1H) 1537

FAB(+) 335 (MH⁺) 137- 142° C. ¹H-NMR(DMSO-d₆) δ ppm: 4.61 and 4.74(s,total 2H), 6.75(d, J=8Hz, 1H), 6.84(m, 1H), 6.94(d, J=8Hz, 1H),7.28-7.41 and 7.55- 7.59(m, total 2H), 7.91-8.02(m, 1H), 8.37-8.45(m,1H), 9.58-9.63(m, 1H) 1538

FAB(+) 296 (M⁺) 197- 198° C. ¹H-NMR(DMSO-d₆) δ ppm: 2.73 and 2.98(s,3H), 4.37 and 4.41(s, total 2H), 6.63 and 6.68(s, total 1H), 6.69 and6.71(d, J=7.8Hz, total 1H), 6.89 and 6.92(d, J=7.8Hz, total 1H), 7.63(s,2H), 8.53 and 8.67(s, total 1H), 9.51 and 9.53(s, total 1H) 1539

FAB(+) 373 (M⁺) 208- 210° C. ¹H-NMR(DMSO-d₆) δ ppm: 4.28 and 4.58(s,total 2H), 4.48(s, 2H), 6.61 and 6.72(d, J=7.8Hz, total 1H), 6.64 and6.67(s, total 1H), 6.83 and 6.90(d, J=7.8Hz, total 1H), 7.26 and 7.36(d,J=8.8Hz, total 1H), 7.28-7.32 and 7.32-7.35(m, total 1H), # 7.62-7.66(m,2H), 7.55- 7.80(d, =8.8Hz, 1H), 8.51 and 8.56(d, J=5.3Hz,total 1H), 8.83and 8.85(s, total 1H), 9.50(s, 1H)

Example 1540N¹,N¹-Dimethyl-N²-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)formamidine

400 mg of 8-(aminomethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine wasdissolved in tetrahydrofuran (5 ml)/methanol (5 ml). After adding 250 mgof N,N-dimethylformamide dimethyl acetal, the resulting mixture washeated to 40° C. for 1.5 hours. After distilling off the solvent underreduced pressure, the crystals thus precipitated were taken up byfiltration and washed successively with diethyl ether and diisopropylether. Thus 400 mg of the title compound was obtained as yellowcrystals.

¹H-NMR(DMSO-d₆) δ ppm: 2.77(s, 6H), 4.15(s, 2H), 6.64(dd, J=1.4, 7.9 Hz,1H), 6.68(d, J=1.4 Hz, 1H), 6.79(d, J=7.9 Hz, 1H), 7.42(s, 1H), 7.61(d,J=2.4 Hz, 1H), 7.62(d, J=2.4 Hz, 1H), 9.44(s, 1H)

MS: ESI(+)286(MH⁺)

m.p.: 218-219° C.

Example 1541N-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-S-methylisothiourea

To a solution of 1.0 g ofN-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)thiourea in acetone(10 ml)/N,N-dimethylformamide (10 ml) was added 1.0 ml of methyl iodideand the resulting mixture was stirred at room temperature for 0.5 hour.Next, the reaction mixture was distributed into an aqueous solution ofpotassium carbonate and ethyl acetate. The organic layer was extractedand washed with water. After distilling off the solvent under reducedpressure, the crystals thus precipitated were taken up by filtration andwashed with ethyl acetate to thereby give 0.900 g of the title compoundas yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 2.25(s, 3H), 4.02 and 4.14(s, total 2H), 6.21 and6.67(br.s, total 2H), 6.68 and 6.69(s, total 1H), 6.75 and 6.80(d, J=8.2Hz, total 1H), 6.79 and 6.85(s, total 1H), 7.58-7.63(m, 2H), 9.51(s, 1H)

Example 15421-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-2-cyanoguanidine

450 mg ofN-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-S-methylisothioureaand 500 mg of cyanamide were heated in 30 ml of N,N-dimethylformamide to70° C. for 12 hours. Then the reaction mixture was brought back to roomtemperature and distributed into water and ethyl acetate. The organiclayer was extracted and washed with water. After adding 5 g of silicagel, the solvent was distilled off under reduced pressure. The residuewas purified by silica gel column chromatography (eluted withdichloromethane/methanol/aqueous ammonia) to thereby give 340 mg of thetitle compound as yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 4.08(d, J=5.0 Hz, 2H), 6.65(d, J=8.4 Hz, 1H),6.66(d, J=1.7 Hz, 1H), 6.68-6.82(br.s, 2H), 6.86(dd, J=1.7, 8.4 Hz, 1H),7.06-7.25(br.s, 1H), 7.62(d, J=2.8 Hz, 1H), 7.63(d, J=2.8 Hz, 1H),9.55(s, 1H)

MS: FAB(+)298(MH⁺), 297(M⁺)

m.p.: 246-248° C.

Example 1543N-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)guanidinehydrochloride

330 mg of 8-aminomethyl-10H-pyrazino[2,3-b][1,4]benzothiazine and 400 mgof methylisothiourea hemi-sulfate were heated under reflux in 10 ml ofethanol for 3 hours. The crystals thus precipitated were taken up byfiltration and washed with ethyl acetate. Then these crystals weredissolved in ethyl acetate containing hydrochloric acid andrecrystallized from methanol/ethyl acetate to thereby give 30 mg of thetitle compound as yellow crystals.

¹H-NMR(DMSO-d₆) δ ppm: 4.20(d, J=6.0 Hz, 2H), 6.67(s, 1H), 6.69(d, J=8.2Hz, 1H), 6.92(d, J=8.2 Hz, 1H), 7.65(s, 2H), (t, J=6.0 Hz, 1H), 9.63(s,1H)

MS: FAB(+)273(MH⁺)

m.p.: 279-282° C.

Examples

The following compounds were obtained by treating8-aminomethyl-10H-pyrazino[2,3-b][1,4]benzothiazine with variousisothiourea compounds by the same method as the one of Example 1543.

Ex. Isothiourea Structural formula MS M.p. NMR 1544

FAB(+) 318(MH⁺) 317(M⁺) 226- 228° C. ¹H-NMR(DMSO-d₆) δ ppm:4.11-4.33(br.s, 2H), 6.67(s, 1H), 6.68(d, J=7.5Hz, 1H), 6.88(d, J=7.5Hz,1H), 7.62(d, J=2.5Hz, 1H), 7.64(d, J=2.5Hz, 1H), 7.70- 8.10(br.s, 2H),8.85- 9.00(br.s, 1H), 9.57(s, 1H) 1545

FAB(+) 350(M⁺) 244- 245° C. ¹H-NMR(DMSO-d₆) δ ppm: 2.78(s, 3H), 4.11(d,J=6.0Hz, 2H), 6.54- 6.78(br.s, 2H), 6.65(s, 1H), 6.68(d, J=7.9Hz, 1H),6.85(d, J=7.9Hz, 1H), 7.02-7.15(br.s, 1H), 7.61-7.64(m, 2H), 9.38(s, 1H)

Example 15468-(1,4,5,6-Tetrahydropyrimidin-1-ylmethyl)-10H-pyrazino[2,3-b][1,4]benzothiazinehydrochloride

The title compound was obtained by reacting8-(chloromethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine by the samemethod as the one of Example 14 by using potassium carbonate as a base.

¹H-NMR(DMSO-d₆) δ ppm: 1.84-1.92(m, 2H), 2.18-2.24(m, 2H), 2.24-2.29(m,2H), 4.48(s, 2H), 6.68(d, J=1.3 Hz, 1H), 6.76(dd, J=1.3, 8.6 Hz, 1H),6.95(d, J=8.6 Hz, 1H), 7.64(s, 2H), 8.43(d, J=6.5 Hz, 1H), 9.58(s, 1H),10.08-10.14(br.s, 1H)

MS: FAB(+)298(MH⁺)

m.p.: 238˜° C.(decompose)

Example 1547N-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-N′-methyl-2-nitro-1,1-ethenediamine

0.7 g of 8-aminomethyl-10H-pyrazino[2,3-b][1,4]-benzothiazine and 1.35 gof N-methyl-1-methylthio-2-nitro-1-ethenamine were dissolved in asolvent mixture of tetrahydrofuran (50 ml) with water (3 ml) and stirredat 60° C. for 8 hours. After filtering off the insoluble matters, thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluted withmethanol/dichloromethane) to thereby give 0.14 g of the title compoundas yellow crystals.

¹H-NMR(CD₃OD) δ ppm: 2.95(br.s, 3H), 4.31(s, 2H), 6.63(s, 2H), 6.74(d,J=8 Hz, 1H), 6.86(d, J=8 Hz, 1H), 7.58(s, 2H)

MS: ESI(+)331(MH⁺)

m.p.: >265° C.(decompose)

Example 15484-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-yl)-3-imino-1,2,5-thiazolidine1,1-dioxide

To 50 ml of a 70% solution of 0.573 g of10H-pyrazino[2,3-b][1,4]benzothiazine-8-carbaldehyde in ethanol wereadded 0.48 g of sulfamide and 0.135 g of sodium cyanide and theresulting mixture was heated under reflux for 6 hours. After distillingoff the solvent under reduced pressure, the residue was dissolved in 50ml of a 10% aqueous solution of sodium hydroxide. After filtering offthe insoluble matters, the filtrate was ice-cooled and the pH valuethereof was adjusted to 2 with 1 N hydrochloric acid. The precipitatethus formed was taken up by filtration and washed with water to therebygive 0.90 g of the title compound as a yellow solid.

¹H-NMR(DMSO-d₆) δ ppm: 5.12(d, J=6 Hz, 1H), 6.76(s, 1H), 6.77(d, J=8 Hz,1H), 6.93(d, J=8 Hz, 1H), 7.54(s, 1H), 7.60(d, J=6 Hz, 1H), 7.65(s, 2H),8.38(s, 1H), 9.65(s, 1H)

MS: FAB(+)357(M⁺)

Example 1549 (5H-Pyrido[3,4-b][1,4]benzothiazin-2-yl)carboxamidinehydrochloride

The title compound was obtained by treating(5H-pyrido[3,4-b][1,4]benzothiazin-2-yl)carboxamide successively by thesame methods as those of Examples 1518 and 1520.

¹H-NMR(DMSO-d₆) δ ppm: 6.84(t, J=7.5 Hz, 1H), 6.89(d, J=7.5 Hz, 1H),6.92(d, J=4.8 Hz, 1H), 7.01(d, J=7.5 Hz, 1H), 7.06(t, J=7.5 Hz, 1H),7.97(d, J=4.8 Hz, 1H), 9.4-9.5(br.s, 2H), 9.5-9.6(br.s, 2H), 9.63(s, 1H)

MS: FAB(+)243(MH⁺)

m.p.: >280° C.

Example 1550Ethyl(E)-3-[10-(tert-butoxycarbonyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl]propenoate

The title compound was obtained by treating3-[10-(tert-butoxycarbonyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl]carbaldehydeby the same method as the one of Production Example 25.

¹H-NMR(CDCl₃) δ ppm: 1.31(t, J=7.1 Hz, 3H), 1.47(s, 9H), 4.25(q, J=7.1Hz, 2H), 6.44(d, J=15.8 Hz, 1H), 7.36(s, 2H), 7.64(d, J=15.8 Hz, 1H),7.82(s, 1H), 8.29(d, J=2.8 Hz, 1H), 8.35(d, J=2.8 Hz, 1H)

Example 1551 Ethyl3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl]propanoate

The title compound was obtained by treatingethyl(E)-3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)propenoate by thesame method as the one of Example 20.

¹H-NMR(CDCl₃) δ ppm: 1.23(t, J=7.1 Hz, 3H), 2.56(t, J=8.0 Hz, 2H),2.80(t, J=8.0 Hz, 2H), 4.12(q, J=7.1 Hz, 2H), 6.36(d, J=1.4 Hz, 1H),6.40-6.48(br.s, 1H), 6.36(d, J=1.4 Hz, 1H), 6.68(dd, J=1.4, 8.1 Hz, 1H),6.81(d, J=8.1 Hz, 1H), 7.57(d, J=3.0 Hz, 1H), 7.69(d, J=3.0 Hz, 1H)

m.p.: 95-97° C.

Example 1552Ethyl(E)-3-[10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl]propenoate

The title compound was obtained by treatingethyl(E)-3-[10-(tert-butoxycarbonyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl]propenoateby the same method as the one of Example 9.

¹H-NMR(DMSO-d₆) δ ppm: 1.23(t, J=6.8 Hz, 3H), 4.16(q, J=6.8 Hz, 2H),6.37(d, J=15.8 Hz, 1H), 6.93(d, J=1.7 Hz, 1H), 6.95(d, J=7.5 Hz, 1H),7.14(dd, J=1.7, 7.5 Hz, 1H), 7.40(d, J=15.8 Hz, 1H), 7.64(d, J=2.8 Hz,1H), 7.65(d, J=2.8 Hz, 1H), 9.54(s, 1H)

m.p.: 177-178° C.

Example 1553 (E)-3-[10H-Pyrazino[2,3-b][1,4]benzothiazin-8-yl]propenoicacid

The title compound was obtained as yellow crystals by hydrolyzingethyl(E)-3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)propenoate by thesame method as the one of Example 18.

¹H-NMR(DMSO-d₆) δ ppm: 6.28(d, J=16.3 Hz, 1H), 6.93(d, J=1.5 Hz, 1H),6.95(d, J=8.1 Hz, 1H), 7.09(dd, J=1.5, 8.1 Hz, 1H), 7.35(d, J=16.3 Hz,1H), 7.64(d, J=2.9 Hz, 1H), 7.65(d, J=2.9 Hz, 1H), 9.54(s, 1H),12.34-12.52(br.s, 1H)

m.p.: 280-281° C.

Example 1554 (10H-Pyrazino[2,3-b][1,4]benzothiazin-8-yl]carbaldehyde

The title compound was obtained as yellow crystals by treating(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl]carbaldehydeby the same method as the one of Example 9.

¹H-NMR(DMSO-d₆) δ ppm: 7.13(d, J=8.1 Hz, 1H), 7.14(d, J=1.5 Hz, 1H),7.19(dd, J=1.5, 8.1 Hz, 1H), 7.65(d, J=2.7 Hz, 1H), 7.67(d, J=2.7 Hz,1H), 9.73(s, 1H), 9.74(s, 1H)

m.p.: 248-252° C.

Example 1555(E)-3-(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)propenenitrile

The title compound was obtained as yellow crystals by treating(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbaldehydeby the same method as the one of Production Example 25.

¹H-NMR(CDCl₃) δ ppm: 3.55(s, 3H), 5.28(s, 2H), 5.84(d, J=17.3 Hz, 1H),7.02(d, J=7.9 Hz, 1H), 7.04(dd, J=1.5, 7.9 Hz, 1H), 7.19(d, J=1.5 Hz,1H), 7.30(d, J=17.3 Hz, 1H), 7.85(d, J=2.9 Hz, 1H), 7.86(d, J=2.9 Hz,1H)

Example 1556(E)-4-(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-3-propen-2-one

The title compound was obtained as yellow crystals by treating(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbaldehydeby the same method as the one of Production Example 25.

¹H-NMR(CDCl₃) δ ppm: 2.39(s, 3H), 3.56(s, 3H), 5.30(s, 2H), 6.66(d,J=16.2 Hz, 1H), 7.03(d, J=8.3 Hz, 1H), 7.15(dd, J=1.6, 8.3 Hz, 1H),7.30(d, J=1.6 Hz, 1H), 7.42(d, J=16.2 Hz, 1H), 7.85(d, J=2.9 Hz, 1H),7.86(d, J=2.9 Hz, 1H)

Example 1557Ethyl(E)-4-[2-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]-benzothiazin-8-yl)vinyl]benzoate

The title compound was obtained as yellow crystals by treating(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carbaldehydeby the same method as the one of Production Example 25.

¹H-NMR(DMSO-d₆) δ ppm: 1.41(t, J=6.7 Hz, 3H), 3.59(s, 3H), 4.38(q, J=6.7Hz, 2H), 5.34(s, 2H), 7.01(d, J=7.9 Hz, 1H), 7.08(d, J=7.9 Hz, 1H),7.08(d, J=15.3 Hz, 1H), 7.13(d, J=15.3 Hz, 1H), 7.17(dd, J=1.6, 7.9 Hz,1H), 7.29(d, J=1.6 Hz, 1H), 7.56(d, J=8.4 Hz, 2H), 7.84(d, J=2.9 Hz,1H), 7.85(d, J=7.9 Hz, 2H), 8.03(d, J=8.4 Hz, 2H)

Examples

The following compounds were obtained by treating(E)-3-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)propenenitrile,(E)-4-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-3-propen-2-oneandethyl(E)-4-[2-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)vinyl]benzoateby the same method as the one of Example 9.

Ex. Structural formula MS NMR 1558

296-299° C. ¹H-NMR(DMSO-d₆) δ ppm: 6.21(d, J=16.8Hz, 1H), 6.84(d,J=1.6Hz, 1H), 6.98(d, J=8.0Hz, 1H), 7.08(d, J=1.6, 8.0Hz, 1H), 7.46(d,J=16.8Hz, 1H), 7.64(d, J=2.8Hz, 1H), 7.65(d, J=2.8Hz, 1H), 9.63(s, 1H)1559

214-215° C. ¹H-NMR(DMSO-d₆) δ ppm: 2.31(s, 3H), 6.54(d, J=16.3Hz, 1H),6.96(d, J=1.4Hz, 1H), 6.97(d, J=8.4Hz, 1H), 7.11(dd, J=1.4, 8.4Hz, 1H),7.40(d, J=16.3Hz, 1H), 7.64(d, J=2.7Hz, 1H), 7.66(d, J=2.7Hz, 1H),9.58(s, 1H) 1560

235-236° C. ¹H-NMR(DMSO-d₆) δ ppm: 1.31(t, J=6.5Hz, 3H), 4.29(q,J=6.5Hz, 2H), 6.94(d, J=8.3Hz, 1H), 6.95(d, J=1.4Hz, 1H), 7.09(dd,J=1.4, 8.3Hz, 1H), 7.12(d, J=16.7Hz, 1H), 7.23(d, J=16.7Hz, 1H), 7.64(d,J=2.2Hz, 1H), 7.65(d, J=2.2Hz, 1H), 7.71(d, J=8.5Hz, 2H), 7.92(d,J=8.5Hz, 2H), 9.57(s, 1H)

Example 1561 (E)-4-[2-(10H-Pyrazino [2,3-b][1,4]benzothiazin-8-yl)vinyl]-benzoic acid

The title compound was obtained as yellow crystals by hydrolyzingethyl(E)-4-[2-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)vinyl]benzoateby the same method as the one of Example 18.

¹H-NMR(DMSO-d₆) δ ppm: 6.93(dd, J=1.6, 8.1 Hz, 1H), 6.95(d, J=1.6 Hz,1H), 7.08(d, J=8.1 Hz, 1H), 7.12(d, J=16.6 Hz, 1H), 7.21(d, J=16.6 Hz,1H), 7.62-7.67(m, 2H), 7.62-7.67(m, 2H), 7.69(d, J=8.1 Hz, 2H), 7.90(d,J=8.1 Hz, 2H), 9.58(s, 1H)

m.p.: 322-325° C.

Example 1562 (10H-Pyrazino[2,3-b][1,4]benzothiazin-8-yl)carboxylic acid

The title compound was obtained as yellow crystals by hydrolyzingmethyl(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carboxylate by the samemethod as the one of Example 18.

¹H-NMR(DMSO-d₆) δ ppm: 6.99(d, J=8.5 Hz, 1H), 7.28(dd, J=1.6, 8.5 Hz,1H), 7.30(d, J=1.6 Hz, 1H), 7.63(d, J=2.5 Hz, 1H), 7.65(d, J=2.5 Hz,1H), 9.63(s, 1H)

m.p.: 321-323° C.(decmpose)

Example 1563(E)-8-(2-Benzenesulfonylvinyl)-10H-pyrazino[2,3-b][1,4]benzothiazine

The title compound was obtained as yellow crystals by treating(E)-8-(2-benzenesulfonylvinyl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazineby the same method as the one of Example 9.

¹H-NMR(DMSO-d₆) δ ppm: 6.87(d, J=1.7 Hz, 1H), 6.97(d, J=8.1 Hz, 1H),7.17(dd, J=1.7, 8.1 Hz, 1H), 7.35(d, J=15.4 Hz, 1H), 7.40(d, J=15.4 Hz,1H), 7.61-7.67(m, 2H), 7.63(d, J=2.9 Hz, 1H), 7.65(d, J=2.9 Hz, 1H),7.69-7.74(m, 1H), 7.88-7.92(m, 2H), 9.57(s, 1H)

m.p. 201-202° C.

Example 1564 8-Vinyl-10H-pyrazino[2,3-b][1,4]benzothiazine

The title compound was obtained as yellow crystals by treating8-vinyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine by thesame method as the one of Example 9.

¹H-NMR(CDCl₃) δ ppm: 5.30(d, J=10.7 Hz, 1H), 5.37(d, J=17.6 Hz, 1H),6.55(dd, J=10.7, 17.6 Hz, 1H), 6.79(d, J=1.6 Hz, 1H), 6.82(d, J=8.5 Hz,1H), 6.99(dd, J=1.6, 8.5 Hz, 1H), 7.16(d, J=3.5 Hz, 1H), 7.59(d, J=3.5Hz, 1H), 11.05-11.15(br.s, 1H)

m.p.: 140-142° C.

Example 1565 1-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-yl)-1,3-butadione

The title compound was obtained as yellow crystals by treating1-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-1,3-butadioneby the same method as the one of Example 9.

¹H-NMR(DMSO-d₆) δ ppm: 2.14 and 2.19(s, total 3H, enol:keto=4:1),4.11(s, initial 2H, keto), 6.34(s, initial 1H, enol), 7.03 and 7.05(d,J=8.1 Hz, total 1H, 4:1), 7.19 and 7.27(d, J=1.8 Hz, total 1H, 1:4),7.32 and 7.33(dd, J=1.8, 8.1 Hz, total 1H, 1:4), 7.64(d, J=3.2 Hz, total1H), 7.66(d, J=3.2 Hz, total 1H), 9.52 and 9.54(br.s, total 1H, 4:1)

m.p.: 218-220° C.

Example 1566 Methyl (anti)-(3-azabicyclo[3.3.1]non-9-yl)acetatehydrochloride

25.6 g of ethyl (anti)-(3-methyl-3-azabicyclo[3.3.1]non-9-yl)acetate wascooled to 0° C. and 25 ml of 1-chloroethyl chloroformate was droppedthereinto. After stirring at the same temperature for 15 minutes, themixture was reacted for an additional 1 hour. Then it was brought backto room temperature and the 1-chloroethyl chloroformate was distilledoff under reduced pressure. 400 ml of methanol was added to the residueand the resulting mixture was heated under reflux for 2 hours. Afterdistilling off the solvent under reduced pressure, 20 ml of methanol and200 ml of ethyl acetate were added to the residue. The crystals thusprecipitated were collected by filtration to thereby give 20 g of methyl(anti)-(3-azabicyclo[3.3.1]non-9-yl)acetate hydrochloride.

¹H-NMR(CDCl₃) δ ppm: 1.62-1.90(m, 5H), 1.91(br.s, 2H), 2.16-2.34(m, 2H),2.51(d, J=8 Hz, 2H), 3.20-3.32(m, 2H), 3.47(dd, J=4, 13 Hz, 2H), 3.66(d,J=1 Hz, 3H), 8.51(br.s, 1H), 10.08(br.s, 1H)

Example 1567 Methyl(anti)-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]non-9-yl]acetate

To 12 ml of a solution of 1.00 g of8-chloromethyl-10H-pyrazino[2,3-b][1,4]benzothiazine in1,2-dichloroethane were added 1.59 g of methyl(anti)-(3-azabicyclo[3.3.1]non-9-yl)acetate hydrochloride and 2.1 ml ofdiisopropylamine and the resulting mixture was heated under reflux for 1hour. Then the reaction mixture was brought back to room temperature andpurified as it was by silica gel column chromatography (eluting withhexane/ethyl acetate) to thereby give 1.24 g of the title compound as ayellow powder.

¹H-NMR(DMSO-d₆) δ ppm: 1.34-1.48(m, 3H), 1.57(br.s, 2H), 1.60-1.76(m,2H), 1.82-1.92(m, 1H), 2.15(br.d, J=10 Hz, 2H), 2.46(d, J=8 Hz, 2H),2.44-2.6(m, 1H), 2.86(br.d, J=10 Hz, 2H), 3.15(s, 2H), 3.56(s, 3H),6.68(dd, J=1, 8 Hz, 1H), 6.71(d, J=1 Hz, 1H), 6.83(d, J=8 Hz, 1H),7.61(d, J=3 Hz, 1H), 7.62(d, J=3 Hz, 1H), 9.55(s, 1H)

m.p.: 127-129° C.

MS: ESI(+)411(MH⁺)

Example 1568(endo,anti)-[3-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]non-9-yl]aceticacid

0.45 g of the title compound was obtained as a yellow powder by treating0.5 g of methyl(anti)-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-methyl)-3-azabicyclo[3.3.1]non-9-yl]acetateby the same method as described in Example 18.

¹H-NMR(DMSO-d₆) δ ppm: 1.34-1.48(m, 3H), 1.58(br.s, 2H), 1.60-1.76(m,2H), 1.80-1.90(m, 1H), 2.14(br.d, J=10 Hz, 2H), 2.33(d, J=8 Hz, 2H),2.44-2.60(m, 1H), 2.85(br.d, J=10 Hz, 2H), 3.15(s, 2H), 6.67(d, J=8 Hz,1H), 6.72(s, 1H), 6.82(d, J=8 Hz, 1H), 7.60(d, J=3 Hz, 1H), 7.62(d, J=3Hz, 1H), 9.54(s, 1H)

m.p.: 215-217° C.

MS: FAB(+)397(MH⁺)

Example 15698-(tert-Butyldimethylsiloxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine

10 g of (10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)methanol wassubjected to the procedure described in Example 179 to thereby give 13 gof the title compound as a yellow solid.

¹H-NMR(CDCl₃) δ ppm: 0.63(s, 6H), 0.88(s, 9H), 4.54(s, 2H), 6.48(s, 1H),6.71(d, J=8 Hz, 1H), 6.80(d, J=8 Hz, 1H), 7.53(s, 1H), 7.64(s, 1H)

Example 157010-Acetyl-8-(tert-butyldimethylsiloxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine

To a solution of 4.0 g of8-(tert-butyldimethylsiloxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazinein 50 ml of N,N-dimethylformamide was added 0.73 g of sodium hydride(60%) and the resulting mixture was stirred for 10 minutes. After adding1.4 ml of acetyl chloride thereto, the resulting mixture was reacted atroom temperature for 10 minutes. After adding water followed byextraction with ethyl acetate, the extract was washed with a saturatedaqueous solution of sodium chloride and dried over anhydrous magnesiumsulfate. After distilling off the solvent under reduced pressure, theresidue was purified by silica gel column chromatography (eluting withethyl acetate/hexane) to thereby give 2.5 g of the title compound as ayellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 0.1(s, 6H), 0.93(s, 9H), 2.28(s, 3H), 4.76(s, 2H),7.24-7.28(m, 1H), 7.38(d, J=8 Hz, 1H), 7.66(d, J=2 Hz, 1H), 8.32(d, J=3Hz, 1H), 8.35(d, J=3 Hz, 1H)

Example 1571(10-Acetyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)methanol

2.5 g of10-acetyl-8-(tert-butyldimethylsiloxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazinewas subjected to the procedure described in Example 181 to thereby give1.0 g of the title compound as an oily substance.

¹H-NMR(CDCl₃) δ ppm: 2.29(s, 3H), 4.73(s, 2H), 7.29(dd, J=2, 8 Hz, 1H),7.33(d, J=8 Hz, 1H), 7.74(m, 1H), 8.25(d, J=3 Hz, 1H), 8.28(d, J=3 Hz,1H)

Example 1572(10-Acetyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carboxaldehyde

1.0 g of (10-acetyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)methanolwas subjected to the procedure described in Example 174 to thereby give0.6 g of the title compound as a pale brown solid.

¹H-NMR(CDCl₃) δ ppm: 2.34(s, 3H), 7.57(d, J=8 Hz, 1H), 7.80(dd, J=2, 8Hz, 1H), 8.22(d, J=2 Hz, 1H), 8.38(d, J=3 Hz, 1H), 8.41(d, J=3 Hz, 1H),10.2(s, 1H)

Example 15734-[1-(10-Acetyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)piperidin-4-yl]-2-methylbutanoicacid

To a solution of 0.13 g of(10-acetyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carboxaldehyde and0.13 g of 4-(piperidin-4-yl)-2-methylbutanoic acid in 20 ml ofacetonitrile were added 51 mg of sodium cyanoborohydride and 0.1 ml ofacetic acid and the resulting mixture was reacted at room temperaturefor 12 hours. The reaction mixture was concentrated under reducedpressure and the residue was purified by silica gel columnchromatography (eluted with methanol/dichloromethane) to thereby give 70mg of the title compound as a colorless oily substance.

¹H-NMR(CD₃OD) δ ppm: 1.14(d, J=7 Hz, 3H), 1.25-1.40(m, 2H), 1.35-1.50(m,3H), 1.50-1.73(m, 2H), 1.93-2.05(m, 2H), 2.30(s, 3H), 2.33-2.45(m, 1H),2.97-3.10(m, 2H), 3.45-3.55(m, 2H), 4.35(s, 2H), 7.46(dd, J=2, 8 Hz,1H), 7.64(d, J=8 Hz, 1H), 7.84(d, J=2 Hz, 1H), 8.45(s, 2H)

MS: FAB(+)441(MH⁺)

Example 157410-(Methoxycarbonyl)-8-(tert-butyldimethylsiloxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine

4.0 g of8-(tert-butyldimethylsiloxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazinewas subjected to the procedure described in Example 1570 but usingmethyl chlorocarbonate instead of acetyl chloride to thereby give 2.5 gof the title compound as a yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 0.1(s, 6H), 0.94(s, 9H), 3.83(s, 3H), 4.75(s, 2H),7.18-7.24(m, 1H), 7.34(d, J=8 Hz, 1H), 7.63(d, J=2 Hz, 1H), 8.3-8.34(m,1H), 8.34-8.38(m, 1H)

Example 1575[10-(Methoxycarbonyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl]methanol

2.5 g of10-(methoxycarbonyl)-8-(tert-butyldimethylsilyloxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazinewas subjected to the procedure described in Example 181 to thereby give1.0 g of the title compound as a yellow oily substance.

¹H-NMR(CDCl₃) δ ppm: 3.84(s, 3H), 4.72-4.76(m, 2H), 7.28(dd, J=2, 8 Hz,1H), 7.39(d, J=8 Hz, 1H), 7.67-7.70(m, 1H), 8.33(d, J=3 Hz, 1H), 8.37(d,J=3 Hz, 1H)

Example 1576[10-(Methoxycarbonyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl]carboxaldehyde

1.8 g of[10-(methoxycarbonyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl]methanolwas subjected to the procedure described in Example 174 to thereby give0.8 g of the title compound as pale brown crystals.

¹H-NMR(CDCl₃) δ ppm: 3.87(s, 3H), 7.54(d, J=8 Hz, 1H), 7.78(dd, J=2, 8Hz, 1H), 8.16(d, J=2 Hz, 1H), 8.36(d, J=3 Hz, 1H), 8.41(d, J=3 Hz, 1H),10.01(s, 1H)

Example 15774-[1-(10-(Methoxycarbonyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)piperidin-4-yl]-2-methylbutanoicacid

0.8 g of[10-(methoxycarbonyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl]carboxaldehydewas subjected to the procedure described in Example 1573 to thereby give0.29 g of the title compound as a yellow amorphous substance.

¹H-NMR(CD₃OD) δ ppm: 1.09(d, J=7 Hz, 3H), 1.20-1.45(m, 5H), 1.45-1.70(m,2H), 1.85-2.0(m, 2H), 2.28-2.40(m, 1H), 2.90-3.0(m, 2H), 3.35-3.50(m,2H), 3.77(s, 3H), 4.29(s, 2H), 7.40(dd, J=2, 8 Hz, 1H), 7.56(d, J=8 Hz,1H), 7.81(d, J=2 Hz, 1H), 8.37(d, J=3 Hz, 1H), 8.38(d, J=3 Hz, 1H)

Example 1578 Methyl (anti)-[3-[10-(methoxycarbonyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-3-azabicyclo[3.3.1]non-9-yl]acetate

1.0 g of methyl(anti)-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]non-9-yl]acetatewas treated in the same manner as the one of Example 1574 to therebygive 0.14 g of the title compound as a pale yellow solid.

¹H-NMR(CDCl₃) δ ppm: 1.4-1.6(m, 3H), 1.62-1.68(m, 2H), 1.68-1.84(m, 2H),2.00-2.08(m, 1H), 2.31(br.d, J=11 Hz, 2H), 2.50(d, J=8 Hz, 2H),2.52-2.68(m, 1H), 2.9-2.98(m, 2H), 3.41(s, 2H), 3.66(s, 3H), 3.83(s,3H), 7.21(dd, J=2, 8 Hz, 1H), 7.32(d, J=8 Hz, 1H), 7.63(d, J=2 Hz, 1H),8.32(d, J=3 Hz, 1H), 8.36(d, J=3 Hz, 1H)

m.p.: 106-108° C.

MS: ESI(+)469(MH⁺)

Example 1579 Methyl(anti)-[3-(10-acetyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]non-9-yl]acetate

1.0 g of methyl(anti)-[3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]non-9-yl]acetatewas subjected to the procedure described in Example 1570 to thereby give0.4 g of the title compound as a pale yellow solid.

¹H-NMR(CDCl₃) δ ppm: 1.44-1.60(m, 3H), 1.60-1.68(m, 2H), 1.68-1.82(m,2H), 1.96-2.08(m, 1H), 2.28(s, 3H), 2.31(br.d, J=11 Hz, 2H), 2.49(d, J=8Hz, 2H), 2.50-2.70(m, 1H), 2.90-2.98(m, 2H), 3.41(s, 2H), 3.66(s, 3H),7.23(dd, J=1, 8 Hz, 1H), 7.36(d, J=8 Hz, 1H), 7.66(s, 1H), 8.3-8.38(m,2H)

m.p.: 160-162° C.

MS: ESI(+)453(MH⁺)

Example 1580 Methyl(anti)-[3-[10-(benzyloxycarbonyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-3-azabicyclo[3.3.1]non-9-yl]acetate

1.0 g of methyl(anti)-[3-(10H-pyrazino[2,3-b][1,4]benzotiazin-8-ylmethyl)-3-azabicyclo[3.3.1]non-9-yl]acetatewas subjected to the procedure described in Example 1570 but usingbenzyl chlorocarbonate instead of acetyl chloride to thereby give 0.4 gof the title compound as a pale brown oily substance.

¹H-NMR(CDCl₃) δ ppm: 1.4-1.6(m, 3H), 1.56-1.66(m, 2H), 1.66-1.80(m, 2H),1.96-2.24(m, 1H), 2.27(br.d, J=11 Hz, 2H), 2.49(d, J=8 Hz, 2H),2.46-2.68(m, 1H), 2.86-2.94(m, 2H), 3.37(s, 2H), 3.67(s, 3H), 5.28(s,2H), 7.10-7.40(m, 7H), 7.61(d, J=1 Hz, 1H), 8.31(d, J=2 Hz, 1H), 8.36(d,J=2 Hz, 1H)

MS: ESI(+)545(MH⁺)

What is claimed is:
 1. A benzopiperidine derivative represented by theformula:

and salts and hydrates thereof, wherein R¹ and R² may be the same ordifferent and each represents hydrogen or C₁₋₆ lower alkyl; and Urepresents: 1) a group represented by the formula:

wherein l and m may be the same or different and each represents 0 or 1;and wherein X and Y each represents C₁₋₆ lower alkylene optionallysubstituted with one to three substituents selected from H, ═O, —OH,—COOH, C₁₋₆ lower alkyl, —C(O)—C₁₋₆ lower alkyl, —C(O)O—C₁₋₆ loweralkyl, C₁₋₆ lower alkoxy, optionally having one to three heteroatomsselected from O, N, or S, C₁₋₆ lower alkenylene optionally substitutedwith one to three substituents selected from H, ═O, —OH, —COOH, C₁₋₆lower alkyl, —C(O)—C₁₋₆ lower alky, —C(O)O—C₁₋₆ lower alkyl, C₁₋₆ loweralkoxy, optionally having one to three heteroatoms selected from O, N,or S, C₁₋₆ lower alkynylene optionally substituted with one to threesubstituents selected from H, ═O, —OH, —COOH, C₁₋₆ lower alkyl,—C(O)—C₁₋₆ lower alkyl, —C(O)O—C₁₋₆ lower alkyl, C₁₋₆ lower alkoxy,optionally having one to three heteroatoms selected from O, N, or S; andwherein the ring A represents a cycloalkyl ring optionally substitutedwith one to three substituents selected from H, ═O, —OH, —COOH, C₁₋₆lower alkyl, —C(O)—C₁₋₆ lower alkyl, —C(O)O—C₁₋₆ lower alkyl, C₁₋₆ loweralkoxy, optionally having one to three heteroatoms selected from O or N;and wherein the ring B represents a ring optionally having one to threedouble bonds in the ring selected from the following ones: a) acycloalkyl ring optionally substituted with one to three substituentsselected from H, ═O, —OH, —COOH, C₁₋₆ lower alkyl, —C(O)—C₁₋₆ loweralkyl, —C(O)O—C₁₋₆ lower alkyl, C₁₋₆ lower alkoxy, optionally having aheteroatom selected from O or N; or b) a bicycloalkyl ring optionallysubstituted with one to three substituents selected from H, ═O, —OH,—COOH, C₁₋₆ lower alkyl, —C(O)—C₁₋₆ lower alkyl, —C(O)O—C₁₋₆ loweralkyl, C₁₋₆ lower alkoxy, optionally having a heteroatom of O or N,wherein bridgehead carbon atoms in the ring B are bonded to each othervia a C₁ or higher alkylene group optionally having a heteroatomselected from O or N; or c) a spiro-cycloalkyl ring optionallysubstituted with one to three substituents selected from H, ═O, —OH,—COOH, C₁₋₆ lower alkyl, —C(O)—C₁₋₆ lower alkyl, —C(O)O—C₁₋₆ loweralkyl, C₁₋₆ lower alkoxy, optionally having a heteroatom of O or N,wherein both ends of a C₁ or higher alkylene group optionally having aheteroatom selected from O or N are bonded to a carbon atom (bridgeheadcarbon atom) in the ring B; or U represents: 2) a group represented bythe following formula:

wherein l¹ is 0 or 1; and wherein X¹ represents C₁₋₆ lower alkylene,C₁₋₆ lower alkenylene, or C₁₋₆ lower alkynylene, which are optionallysubstituted with a substituent selected from H, ═O, —OH, —COOH, C₁₋₆lower alkyl, —C(O)—C₁₋₆ lower alkyl, —C(O)O—C₁₋₆ lower alkyl, C₁₋₆ loweralkoxy, optionally having one to three heteroatoms selected from O, N,or S; and wherein the ring A¹ represents: a) a cycloalkyl ringoptionally substituted with a substituent selected from H, ═O, —OH,—COOH, C₁₋₆ lower alkyl, —C(O)—C₁₋₆ lower alkyl, —C(O)O—C₁₋₆ loweralkyl, C₁₋₆ lower alkoxy, optionally having a heteroatom selected fromO, N, and S; or b) a bicycloalkyl ring optionally substituted with oneto three substituents selected from H, ═O, —OH, —COOH, C₁₋₆ lower alky,—C(O)—C₁₋₆ lower alkyl, —C(O)O—C₁₋₆ lower alkyl, C₁₋₆ lower alkoxy,optionally having a heteroatom selected from O, N, and S; or c) aspiro-cycloalkyl ring optionally having a heteroatom selected from O, N,and S, wherein both ends of an optionally substituted C₁ or higheralkylene group optionally having a heteroatom selected from O, N, and Sare bonded to a carbon atom (bridgehead carbon atom) in the ring A¹; orU represents 3) nitroso; or U represents 4) a group represented by theformula:

 wherein R⁹⁰ and R⁹¹ represent each hydrogen or C₁₋₆ lower alkyl; Rrepresents: 1) hydrogen; 2) C₁₋₆ lower alkyl; 3) aryl C₁₋₆ lower alkyl;4) heteroaryl C₁₋₆ lower alkyl, wherein a heteroatom is selected form O,N, and S; 5) a group represented by the following formula:

 wherein X³ represents C₁₋₆ lower alkylene optionally having aheteroatom selected from O, N, and S, C₁₋₆ lower alkenylene optionallyhaving a heteroatom selected from O, N, and S, or C₁₋₆ lower alkynyleneoptionally having a heteroatom selected from O, N, and S; and R⁹ and R¹⁰may be the same or different and each represents hydrogen, C₁₋₆ loweralkyl, or an amino protective group; or 6) a group represented by theformula: —X⁴—CO₂R¹¹  wherein X⁴ represents C₁₋₆ lower alkyleneoptionally having a heteroatom selected from O, N, and S, C₁₋₆ loweralkenylene optionally having a heteroatom selected from O, N, and S, orC₁₋₆ lower alkynylene optionally having a heteroatom selected from O, N,and S; and R¹¹ represents hydrogen, C₁₋₆ lower alkyl, or a carboxyprotective group; and n represents 0, 1, or
 2. 2. The benzopiperidinederivative as set forth in claim 1, its salt or hydrates thereof,wherein U represents: 1) a group represented by the formula:

 wherein X, Y, l, m, and the ring B are each as defined in claim 1; andthe ring A² represents an optionally substituted cycloalkyl ring havingone or more heteroatoms; or 2) a group represented by the formula:

 wherein X¹ and l¹ are each as defined in claim 1; and the ring A³represents: a) an optionally substituted cycloalkyl ring having one ormore heteroatoms; b) an optionally substituted cycloalkenyl ring havingone or more heteroatoms; or c) an optionally substitutedspiro-hydrocarbon ring having one or more heteroatoms, wherein the bothends of an optionally substituted C₁ or higher alkylene group optionallyhaving a heteroatom are bonded to a carbon atom (bridgehead carbon atom)in the ring A³.
 3. A benzopiperidine derivative represented by theformula (III), its salt or hydrates thereof:

wherein R is as defined in claim 1 and the ring G represents anoptionally substituted heteroaryl ring having one or more nitrogenatoms; U¹ represents: 1) a group represented by the formula:

 wherein Y, m and the rings A² and B are each as defined in claim 2; or2) a group represented by the following formula:

 wherein the ring A³ is as defined in claim
 2. 4. The benzopiperidinederivative as set forth in any of claim 2, 3, or 1, its salt or hydratesthereof, wherein the ring G is an optionally substituted pyrazine ring.5. The benzopiperidine derivative as set forth in claim 1 selected fromamong those represented by the formulae 1) to 3):

or a salt thereof or a hydrate thereof.
 6. The benzopiperidinederivative as set forth in claim 5, which is represented by the formula